NZ795530A - Amine-substituted heterocyclic compounds as ehmt2 inhibitors and methods of use thereof - Google Patents

Abstract

The present disclosure relates to amine-substituted heterocyclic compounds. The present disclosure also relates to pharmaceutical compositions containing these compounds and methods of treating a disorder (e.g., cancer) via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2, by administering an amine-substituted heterocyclic heterocyclic compound disclosed herein or a pharmaceutical composition thereof to subjects in need thereof. The present disclosure also relates to the use of such compounds for research or other non-therapeutic purposes. administering an amine-substituted heterocyclic heterocyclic compound disclosed herein or a pharmaceutical composition thereof to subjects in need thereof. The present disclosure also relates to the use of such compounds for research or other non-therapeutic purposes.

Description

The present disclosure relates to substituted heterocyclic compounds. The present disclosure also relates to pharmaceutical compositions ning these compounds and methods of treating a disorder (e.g., cancer) via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2, by administering an amine-substituted heterocyclic heterocyclic compound disclosed herein or a pharmaceutical composition f to subjects in need thereof. The present disclosure also relates to the use of such compounds for research or other non-therapeutic purposes.

NZ 795530 Attorney Docket No.: EPIZ-073/001WO (311622-2509) AMINE-SUBSTITUTED HETEROCYCLIC COMPOUNDS AS EHMT2 INHIBITORS AND METHODS OF USE THEREOF RELATED APPLICATION This application claims priority to U.S. Application Nos. 62/517,840, filed June 9, 2017, and ,139, filed December 19, 2016, the entire contents of each of which are incorporated herein by reference.

BACKGROUND Methylation of protein lysine residues is an important signaling mechanism in eukaryotic cells, and the methylation state of histone lysines encodes signals that are ized by a multitude of proteins and protein complexes in the context of epigenetic gene regulation.

Histone methylation is catalyzed by histone methyltransferases (HMTs), and HMTs have been implicated in s human es. HMTs can play a role in either activating or repressing gene expression, and certain HMTs (e.g., euchromatic histone-lysine N- methyltransferase 2 or EHMT2, also called G9a) may methylate many nonhistone proteins, such as tumor suppressor proteins (see, e.g., Liu et al., l of Medicinal Chemistry 56:8931-8942, 2013 and Krivega et al., Blood 126(5):665-672, 2015).

Two related HMTs, EHMT1 and EHMT2, are overexpressed or play a role in diseases and disorders such as sickle cell anemia (see, e.g., ille et al., Blood 126(16): 1930–1939, 2015) and proliferative disorders (e.g., cancers), and other blood disorders.

SUMMARY In one aspect, the present sure features an amine-substituted heterocyclic nd of any of Formulae (I0)-(IV0) below: (I0), Attorney Docket No.: EPIZ-073/001WO (311622-2509) (II0), X8 X5 R14 R9 N X6 R7 (III0), or (IV0), or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein X1 is N or CR2; X2 is N or CR3; X3 is N or CR4; X4 is N or CR5; X5 is N or CH; X6 is N or CR15; X7 is N or CH; X8 is NR13 or CR11R12; one of X13 and X14 independently is NR8R9, and the other is R10; B is C6-C10 aryl or 5- to 10-membered heteroaryl optionally tuted with one or more R1 is H or C1-C4 alkyl; each of R2, R3, R4, and R5, independently is selected from the group consisting of H, halo, cyano, C1-C6 alkoxyl, C6-C10 aryl, OH, NRaRb, C(O)NRaRb, NRaC(O)Rb, C(O)ORa, OC(O)Ra, OC(O)NRaRb, NRaC(O)ORb, C3-C8 lkyl, 4- to 7- membered cycloalkyl, 5- to 6- membered heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, n the C6-C10 aryl, C3- C8 cycloalkyl, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, C1-C6 alkoxyl, Attorney Docket No.: 73/001WO (311622-2509) C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, are each optionally substituted with one or more of halo, ORa, or NRaRb, in which each of Ra and Rb independently is H or C1-C6 alkyl; R6 is –Q1-T1, in which Q1 is a bond, or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C1-C6 alkoxyl, and T1 is H, halo, cyano, or RS1, in which RS1 is C3-C8 cycloalkyl, phenyl, 4- to 12- membered heterocycloalkyl containing 1-4 atoms selected from N, O, and S, or a 5- or 6- ed heteroaryl and RS1 is optionally substituted with one or more of halo, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, hydroxyl, oxo, -C(O)Rc, -C(O)ORc, -SO2Rc, -SO2N(Rc)2, -NRcC(O)Rd, -C(O)NRcRd, O)ORd, -OC(O)NRcRd, NRcRd, or C1-C6 alkoxyl, in which each of Rc and Rd independently is H or C1-C6 alkyl; R7 is –Q2-T2, in which Q2 is a bond, C(O)NRe, or NReC(O), Re being H or C1-C6 alkyl and T2 is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl, and wherein the 5- to -membered heteroaryl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more –Q3-T3, wherein each Q3 independently is a bond or C1-C3 alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 , and each T3 ndently is ed from the group consisting of H, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORf, C(O)Rf, C(O)ORf, OC(O)Rf, S(O)2Rf, NRfRg, OC(O)NRfRg, NRfC(O)ORg, fRg, and NRfC(O)Rg, each of Rf and Rg independently being H, C3-C8 cycloalkyl, or C1-C6 alkyl optionally substituted with C3-C8 cycloalkyl, in which the C3-C8 cycloalkyl, C6-C10 aryl, 4- to ered heterocycloalkyl or 5- to 6-membered heteroaryl is optionally substituted with one or more halo, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy; or –Q3-T3 is oxo; R8 is H or C1-C6 alkyl; R9 is –Q4-T4, in which Q4 is a bond or C1-C6 alkylene, C2-C6 lene, or C2-C6 alkynylene linker each ally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T4 is H, halo, ORh, NRhRi, NRhC(O)Ri, C(O)NRhRi, C(O)Rh, C(O)ORh, )ORi, OC(O)NRhRi, S(O)2Rh, S(O)2NRhRi, or RS2, in which each of Rh and Ri independently is H or C1-C6 alkyl, and RS2 is C3-C8 cycloalkyl, C6-C10 aryl, 4- to 12-membered cycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and RS2 is optionally substituted with one or more –Q5-T5, wherein each Q5 independently is a bond or C1-C3 alkylene linker each optionally substituted with one or more of Attorney Docket No.: EPIZ-073/001WO (311622-2509) halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T5 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORj, C(O)Rj, C(O)ORj, OC(O)Rj, S(O)2Rj, NRjRk, OC(O)NRjRk, )ORk, C(O)NRjRk, and NRjC(O)Rk, each of Rj and Rk independently being H or C1-C6 alkyl; or –Q5-T5 is oxo; R10 is halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, or 4- to 12- membered heterocycloalkyl ning 1-4 heteroatoms selected from N, O, and S, wherein each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, and 4- to 12-membered heterocycloalkyl is ally substituted with one or more halo, cyano, hydroxyl, oxo, amino, mono- or di- mino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C(O)NRjRk, or NRjC(O)Rk; R11 and R12 together with the carbon atom to which they are attached form a C3-C12 cycloalkyl or 4- to 12-membered heterocycloalkyl containing 1-4 atoms ed from N, O, and S, wherein the C3-C12 cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, C1-C6 alkyl, C2-C6 l, C2-C6 alkynyl, hydroxyl, oxo, amino, mono- or di- alkylamino, or C1-C6 alkoxyl; R13 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, or 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S; R14 is H, halo, cyano, P(O)RlRm, C1-C6 alkyl, C2-C6 l, C2-C6 alkynyl, C3-C12 cycloalkyl, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, or –OR6, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more of halo or OR6, and each of Rl and Rm independently is C1-C6 alkyl; and R15 is H, halo, cyano, or –OR6.

Subsets of the compounds of Formulae (I0)-(IV0) include those of Formulae (I)-(III): Attorney Docket No.: EPIZ-073/001WO (311622-2509) (II), or (III), or a tautomer thereof, or a pharmaceutically acceptable salt of the nd or the tautomer, wherein X1 is N or CR2; X2 is N or CR3; X3 is N or CR4; X4 is N or CR5; X5 is N or CH; X6 is N or CR15; X7 is N or CH; one of X13 and X14 independently is NR8R9, and the other is R10; B is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with one or more R1 is H or C1-C4 alkyl; each of R2, R3, R4, and R5, independently is ed from the group consisting of H, halo, cyano, C1-C6 alkoxyl, C6-C10 aryl, OH, NRaRb, C(O)NRaRb, )Rb, C(O)ORa, OC(O)Ra, OC(O)NRaRb, NRaC(O)ORb, C3-C8 cycloalkyl, 4- to 7- membered heterocycloalkyl, 5- to 6- membered aryl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein the C6-C10 aryl, C3- C8 cycloalkyl, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, C1-C6 alkoxyl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, are each optionally tuted with one or more of halo, ORa, or NRaRb, in which each of Ra and Rb independently is H or C1-C6 alkyl; R6 is –Q1-T1, in which Q1 is a bond, or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C1-C6 alkoxyl, and T1 is H, halo, cyano, or RS1, in which RS1 is C3-C8 cycloalkyl, phenyl, 4- to 12- Attorney Docket No.: EPIZ-073/001WO (311622-2509) membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6- membered heteroaryl and RS1 is optionally substituted with one or more of halo, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, hydroxyl, oxo, -C(O)Rc, -C(O)ORc, -SO2Rc, -SO2N(Rc)2, -NRcC(O)Rd, RcRd, -NRcC(O)ORd, -OC(O)NRcRd, NRcRd, or C1-C6 alkoxyl, in which each of Rc and Rd independently is H or C1-C6 alkyl; R7 is –Q2-T2, in which Q2 is a bond, C(O)NRe, or NReC(O), Re being H or C1-C6 alkyl and T2 is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl, and wherein the 5- to bered heteroaryl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more –Q3-T3, wherein each Q3 independently is a bond or C1-C3 alkylene linker each optionally substituted with one or more of halo, cyano, yl, or C1-C6 alkoxy, and each T3 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C2-C6 l, C2-C6 alkynyl, C3-C8 lkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 atoms selected from N, O, and S, 5- to 6-membered aryl, ORf, C(O)Rf, C(O)ORf, f, f, NRfRg, OC(O)NRfRg, NRfC(O)ORg, C(O)NRfRg, and NRfC(O)Rg, each of Rf and Rg independently being H, C3-C8 cycloalkyl, or C1-C6 alkyl optionally substituted with C3-C8 cycloalkyl, in which the C3-C8 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl or 5- to 6-membered heteroaryl is ally substituted with one or more halo, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy; or –Q3-T3 is oxo; R8 is H or C1-C6 alkyl; R9 is –Q4-T4, in which Q4 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T4 is H, halo, ORh, NRhRi, NRhC(O)Ri, C(O)NRhRi, C(O)Rh, C(O)ORh, NRhC(O)ORi, OC(O)NRhRi, S(O)2Rh, S(O)2NRhRi, or RS2, in which each of Rh and Ri independently is H or C1-C6 alkyl, and RS2 is C3-C8 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and RS2 is optionally substituted with one or more , n each Q5 independently is a bond or C1-C3 alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T5 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to ered heteroaryl, ORj, C(O)Rj, C(O)ORj, OC(O)Rj, S(O)2Rj, NRjRk, OC(O)NRjRk, Attorney Docket No.: EPIZ-073/001WO (311622-2509) )ORk, C(O)NRjRk, and NRjC(O)Rk, each of Rj and Rk independently being H or C1-C6 alkyl; or –Q5-T5 is oxo; R10 is halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, or 4- to 12- membered cycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 l, C3-C8 cycloalkyl, and 4- to 12-membered heterocycloalkyl is optionally substituted with one or more halo, cyano, hydroxyl, oxo, amino, mono- or di- alkylamino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C(O)NRjRk, or NRjC(O)Rk; R11 and R12 together with the carbon atom to which they are attached form a C3-C12 cycloalkyl or 4- to bered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, n the C3-C12 cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, oxo, amino, mono- or di- alkylamino, or C1-C6 alkoxyl; and R15 is H, halo, cyano, or –OR6.

Subsets of the compounds of Formula (I0) include those of Formulae (I0a)-(I0l): (I0a), (I0b), (I0c), (I0d), Attorney Docket No.: EPIZ-073/001WO (311622-2509) (I0e), (I0f), (I0g), (I0h), (I0i), (I0j), (I0k), (I0l), and tautomers thereof, and pharmaceutically acceptable salts of the compounds and the ers.

Subsets of the compounds of Formula (I0) include those of Formulae (I0a’)-(I0i’): (I0a’), (I0b’), (I0c’), (I0d’), Attorney Docket No.: EPIZ-073/001WO (311622-2509) (I0e’), , (I0g’), (I0h’), (I0i’), and tautomers thereof, and pharmaceutically acceptable salts of the compounds and the tautomers.

Subsets of the compounds of a (I) include those of Formulae (Ia)-(Il): (Ia), (Ib), (Ic), (Id), Attorney Docket No.: EPIZ-073/001WO (311622-2509) R4 OR6 N N N R7 R9 R1 (Ie), (If), (Ig), (Ih), N N N N R7 R9 R2 R1 (Ii), (Ij), (Ik), (Il), and tautomers thereof, and pharmaceutically able salts of the compounds or the tautomers.

Subsets of the compounds of Formula (I) include those of Formulae (Ia’)-(Ii’): (Ia’), (Ib’), (Ic’), (Id’), Attorney Docket No.: EPIZ-073/001WO (311622-2509) (Ie’), (If’), (Ig’), (Ih’), (Ii’), and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers.

Subsets of the compounds of Formula (II0) include those of ae (II0a) and (II0b): X5 R14 N N X6 R7 R9 (II0a), (II0b), and tautomers f, and pharmaceutically able salts of the compounds or the tautomers.

Subsets of the compounds of Formula (III0) include those of Formulae (III0a) and (III0b): (III0a), (III0b), and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers.

Attorney Docket No.: EPIZ-073/001WO 2-2509) Subsets of the compounds of Formula (IV0) include those of Formulae (IV0a) and (IV0b): (IV0a), (IV0b), and ers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers.

Subsets of the compounds of Formula (II) include those, wherein (i) each of X5, X6 and X7 is CH; (ii) at least one of X5, X6 and X7 is N; or (iii) at most one of X5, X6 and X7 is N, and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers.

Subsets of the compounds of Formula (III) include those, wherein (i) each of X5 and X6 is CH; (ii) each of X5 and X6 is N; or (iii) one of X5 and X6 is CH and the other is CH, and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the ers.

In some embodiments, one or more of the compounds disclosed herein are selective inhibitors of EHMT2. In some embodiments, one or more of the compounds disclosed herein t EHMT2 with an enzyme inhibition IC50 value of about 1 µM or less, about 500 nM or less, about 200 nM or less, about 100 nM or less, or about 50 nM or less.

In some embodiments, one or more of the compounds disclosed herein inhibit a kinase with an enzyme inhibition IC50 value of about 100 nM or greater, 1 µM or greater, 10 µM or greater, 100 µM or greater, or 1000 µM or greater.

In some embodiments, one or more of the nds disclosed herein inhibit a kinase with an enzyme inhibition IC50 value of about 1 mM or greater.

In some embodiments, one or more of the nds disclosed herein inhibit a kinase with an enzyme inhibition IC50 value of 1 µM or greater, 2 µM or greater, 5 µM or greater, or 10 µM or greater, wherein the kinase is one or more of the following: AbI, AurA, CHK1, MAP4K, IRAK4, JAK3, EphA2, FGFR3, KDR, Lck, MARK1, MNK2, PKCb2, SIK, and Src.

Also provided herein are pharmaceutical compositions comprising one or more pharmaceutically acceptable carriers and one or more nds of any of the Formulae sed herein, such as ae (I0)-(IV0) and Formulae (I)-(III) described herein.

Another aspect of this disclosure is a method of preventing or treating an EHMT-mediated disorder. The method includes administering to a subject in need thereof a eutically effective amount of a compound of any of the Formulae disclosed herein, such as Formulae (I0)- (IV0) and Formulae (I)-(III), or a tautomer thereof, or a pharmaceutically acceptable salt of the Attorney Docket No.: EPIZ-073/001WO (311622-2509) compound or the tautomer. The EHMT-mediated disorder is a disease, disorder, or condition that is mediated at least in part by the activity of EHMT1 or EHMT2 or both. In one ment, the EHMT-mediated disorder is a blood disease or disorder. In certain embodiments, the EHMT- mediated disorder is selected from proliferative disorders (e.g., cancers such as leukemia, hepatocellular carcinoma, prostate oma, and lung cancer), addiction (e.g., cocaine addiction), and mental retardation.

Unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such ent or laxis as is described herein, as well as use of the nds to prepare a medicament to treat or prevent such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models. Methods described herein may be used to identify suitable candidates for treating or preventing EHMT- mediated disorders. For example, the disclosure also provides methods of identifying an inhibitor of EHMT1 or EHMT2 or both.

For example, the ediated disease or disorder comprises a disorder that is associated with gene silencing by EHMT1 or EHMT2, e.g., blood diseases or disorders associated with gene silencing by EHMT2.

For example, the method comprises the step of administering to a subject having a disease or disorder associated with gene silencing by EHMT1 or EHMT2 a therapeutically ive amount of one or more compounds of the ae described herein, wherein the compound(s) inhibits histone methyltransferase activity of EHMT1 or EHMT2, thereby treating the disease or disorder.

For e, the blood disease or er is selected from the group consisting of sickle cell anemia and beta-thalassemia.

For e, the blood disease or disorder is hematological cancer.

For example, the hematological cancer is acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL).

For example, the method further comprises the steps of performing an assay to detect the degree of histone methylation by EHMT1 or EHMT2 in a sample comprising blood cells from a subject in need thereof.

In one embodiment, performing the assay to detect methylation of H3-K9 in the histone substrate comprises measuring incorporation of labeled methyl groups.

In one ment, the labeled methyl groups are ically labeled methyl groups.

Attorney Docket No.: EPIZ-073/001WO (311622-2509) In one ment, performing the assay to detect methylation of H3-K9 in the histone substrate comprises ting the histone substrate with an antibody that binds specifically to ylated H3-K9.

Still another aspect of the disclosure is a method of inhibiting conversion of H3-K9 to dimethylated H3-K9. The method comprises the step of contacting a mutant EHMT, the wild-type EHMT, or both, with a histone substrate comprising H3-K9 and an effective amount of a compound of the present disclosure, wherein the compound inhibits histone methyltransferase activity of EHMT, thereby inhibiting conversion of H3-K9 to dimethylated H3-K9.

Further, the compounds or methods described herein can be used for research (e.g., studying epigenetic enzymes) and other non-therapeutic es.

In some aspects, the present disclosure provides a compound disclosed herein for use in preventing or treating a blood disorder via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2.

In some aspects, the present disclosure es a compound disclosed herein for use in preventing or treating a cancer via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2.

In some aspects, the present sure provides use of a compound disclosed herein in manufacture of a medicament for preventing or treating a blood disorder via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2.

In some aspects, the present disclosure provides use of a compound disclosed herein in manufacture of a medicament for preventing or treating a cancer via tion of a methyltransferase enzyme selected from EHMT1 and EHMT2.

Unless otherwise defined, all technical and ific terms used herein have the same g as commonly understood by one of ry skill in the art to which this disclosure belongs. In the specification, the ar forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and als are bed below. All ations, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and es are illustrative only and Attorney Docket No.: EPIZ-073/001WO 2-2509) are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will l.

Other features and advantages of the disclosure will be apparent from the following detailed ption and claims.

DETAILED DESCRIPTION The present disclosure provides novel amine-substituted heterocyclic compounds, synthetic methods for making the compounds, pharmaceutical compositions containing them and various uses of the compounds.

In one aspect, the compounds disclosed herein may be used to treat a blood disorder, e.g., sickle-cell anemia (i.e., sickle-cell e). Non-limiting examples of sickle-cell anemia forms that may be treated using the contemplated compounds include obin SS disease, hemoglobin SC disease, hemoglobin Sβ0 thalassemia disease, hemoglobin Sβ+ thalassemia disease, hemoglobin SD disease, and hemoglobin SE disease.

Without wishing to be bound by any , it is ed that sickle-cell anemia describes a group of inherited red blood cell disorders in which at least some of the red blood cells of a t having sickle-cell anemia contain hemoglobin S ("HbS"). obin S is a mutated, abnormal form of adult hemoglobin. Without g to be bound by any theory, it is believed that the contemplated compounds may treat sickle cell anemia by inducing fetal hemoglobin ("HbF") expression. See, e.g., Renneville et al., Blood 126(16): 1930–1939, 2015, the content of which is orated herein by reference in its ty.

In some embodiments, one or more complications of sickle-cell anemia may be treated or prevented using the contemplated compounds disclosed . Non-limiting examples of complications that may be treated or prevented using the contemplated compounds include anemia (e.g., severe anemia), hand-foot syndrome, splenic sequestration, delayed developmental growth, eye disorders (e.g., vision loss caused by, e.g., ges in blood vessels supplying the eyes), skin ulcers (e.g., leg ulcers), heart disease, chest syndrome (e.g., acute chest syndrome), priapism, and pain.

The present disclosure provides compounds of any of Formulae (I0)-(IV0) below: Attorney Docket No.: EPIZ-073/001WO (311622-2509) (I0), (II0), R8 X8 X5 R14 R9 N X6 R7 (III0), or (IV0), or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the er, wherein X1 is N or CR2; X2 is N or CR3; X3 is N or CR4; X4 is N or CR5; X5 is N or CH; X6 is N or CR15; X7 is N or CH; X8 is NR13 or CR11R12; one of X13 and X14 independently is NR8R9, and the other is R10; B is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with one or more R1 is H or C1-C4 alkyl; Attorney Docket No.: EPIZ-073/001WO 2-2509) each of R2, R3, R4, and R5, independently is selected from the group consisting of H, halo, cyano, C1-C6 alkoxyl, C6-C10 aryl, OH, NRaRb, C(O)NRaRb, NRaC(O)Rb, a, OC(O)Ra, OC(O)NRaRb, NRaC(O)ORb, C3-C8 cycloalkyl, 4- to 7- membered heterocycloalkyl, 5- to 6- membered heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein the C6-C10 aryl, C3- C8 cycloalkyl, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, C1-C6 alkoxyl, C1-C6 alkyl, C2-C6 l, and C2-C6 alkynyl, are each optionally substituted with one or more of halo, ORa, or NRaRb, in which each of Ra and Rb independently is H or C1-C6 alkyl; R6 is –Q1-T1, in which Q1 is a bond, or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C1-C6 alkoxyl, and T1 is H, halo, cyano, or RS1, in which RS1 is C3-C8 cycloalkyl, phenyl, 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6- membered aryl and RS1 is optionally substituted with one or more of halo, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, hydroxyl, oxo, -C(O)Rc, Rc, -SO2Rc, -SO2N(Rc)2, -NRcC(O)Rd, -C(O)NRcRd, O)ORd, -OC(O)NRcRd, NRcRd, or C1-C6 alkoxyl, in which each of Rc and Rd independently is H or C1-C6 alkyl; R7 is –Q2-T2, in which Q2 is a bond, C(O)NRe, or NReC(O), Re being H or C1-C6 alkyl and T2 is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl, and wherein the 5- to -membered heteroaryl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more –Q3-T3, wherein each Q3 independently is a bond or C1-C3 alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T3 ndently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 lkyl, C6-C10 aryl, 4- to 7-membered cycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORf, C(O)Rf, f, OC(O)Rf, S(O)2Rf, NRfRg, OC(O)NRfRg, NRfC(O)ORg, C(O)NRfRg, and NRfC(O)Rg, each of Rf and Rg independently being H, C3-C8 cycloalkyl, or C1-C6 alkyl ally substituted with C3-C8 cycloalkyl, in which the C3-C8 lkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl or 5- to 6-membered aryl is optionally substituted with one or more halo, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy; or –Q3-T3 is oxo; R8 is H or C1-C6 alkyl; R9 is –Q4-T4, in which Q4 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T4 is H, halo, ORh, NRhRi, NRhC(O)Ri, C(O)NRhRi, C(O)Rh, C(O)ORh, Attorney Docket No.: EPIZ-073/001WO (311622-2509) )ORi, OC(O)NRhRi, S(O)2Rh, RhRi, or RS2, in which each of Rh and Ri independently is H or C1-C6 alkyl, and RS2 is C3-C8 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 atoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and RS2 is optionally substituted with one or more –Q5-T5, wherein each Q5 independently is a bond or C1-C3 alkylene linker each optionally tuted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T5 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, ORj, C(O)Rj, C(O)ORj, OC(O)Rj, S(O)2Rj, NRjRk, OC(O)NRjRk, NRjC(O)ORk, C(O)NRjRk, and NRjC(O)Rk, each of Rj and Rk independently being H or C1-C6 alkyl; or –Q5-T5 is oxo; R10 is halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, or 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, and 4- to 12-membered heterocycloalkyl is ally substituted with one or more halo, cyano, hydroxyl, oxo, amino, mono- or di- alkylamino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C(O)NRjRk, or NRjC(O)Rk; R11 and R12 together with the carbon atom to which they are attached form a C3-C12 lkyl or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein the C3-C12 cycloalkyl or 4- to 12-membered heterocycloalkyl is ally substituted with one or more of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, oxo, amino, mono- or di- alkylamino, or C1-C6 alkoxyl; R13 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 l, C3-C12 cycloalkyl, or 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S; and R14 is H, halo, cyano, P(O)RlRm, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 4- to 7- membered heterocycloalkyl, 5- to ered heteroaryl, or –OR6, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 l is ally substituted with one or more of halo or OR6, and each of Rl and Rm independently is C1-C6 alkyl; and R15 is H, halo, cyano, or –OR6.

The present disclosure also provides compounds of any of Formulae (I)-(III) below: Attorney Docket No.: EPIZ-073/001WO (311622-2509) (II), or (III), or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.

The compounds of the Formulae disclosed herein, such as Formulae (I0)-(IV0) and Formulae (I)-(III) may include one or more of the following features when applicable.

In some embodiments, the compound is of Formula (III0), in which X8 is NR13.

In some embodiments, R13 is H, C1-C6 alkyl, C3-C12 cycloalkyl (e.g., C3-C8 cycloalkyl), or 4- to 12-membered heterocycloalkyl (e.g., 4- to 7-membered heterocycloalkyl) containing 1-4 heteroatoms ed from N, O, and S (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, lidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, ydro-2H-pyranyl, 3,6-dihydro-2H- pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, morpholinyl, etc.) In some embodiments, R13 is C2-C6 alkenyl or C2-C6 l.

In some embodiments, the compound is of Formula (III0), in which X8 is CR11R12.

In some ments, the compound is of Formula (I0), (II0), or (IV0), in which R14 is H, halo, or C1-C6 alkyl.

In some embodiments, the compound is of Formula (I0), (II0), or (IV0), in which R14 is C2-C6 alkenyl or C2-C6 alkynyl.

In some ments, the compound is of Formula (I0), (II0), or (IV0), in which R14 is – In some embodiments, R14 is H.

Attorney Docket No.: EPIZ-073/001WO (311622-2509) In some embodiments, R14 is halo (e.g., F, Cl, Br, or I). In some embodiments, R14 is F.

In some embodiments, R14 is Cl. In some embodiments, R14 is Br. In some embodiments, R14 is I.

In some embodiments, R14 is cyano.

In some ments, R14 is P(O)RlRm, n each of Rl and Rm independently is C1- C6 alkyl (e.g., each of Rl and Rm is CH3).

In some embodiments, R14 is C1-C6 alkyl optionally substituted with one or more of halo or OR6. In some embodiments, R14 is C1-C6 alkyl (e.g., CH3). In some embodiments, R14 is C1-C6 alkyl substituted with one or more halo (e.g., CF3). In some embodiments, R14 is C1-C6 alkyl substituted with one or more OR6. In some embodiments, R14 is C1-C6 alkyl substituted with one or more OCH3.

In some embodiments, R14 is C3-C12 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

In some embodiments, R14 is 4- to 7- membered heterocycloalkyl (e.g., yl, or tetrahydrofuranyl).

In some embodiments, R14 is 5- to 6-membered heteroaryl (e.g., isoxazolyl).

In some embodiments, R14 is -OR6 (e.g., OCH3).

In some embodiments, R15 is H.

In some embodiments, R15 is halo (e.g., F, Cl, Br, or I). In some embodiments, R15 is F.

In some embodiments, R15 is Cl. In some embodiments, R15 is Br. In some ments, R15 is I.

In some embodiments, R15 is cyano.

In some embodiments, R15 is –OR6 (e.g., OCH3).

In some embodiments, the nd is of Formula (I0) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.

In some embodiments, at least one of X1, X2, X3 and X4 is N.

In some embodiments, X1 and X3 are N. In some embodiments, X2 is CR3 and X4 is CR5.

Attorney Docket No.: EPIZ-073/001WO (311622-2509) In some embodiments, is , , , , , or .

In some embodiments, is , , , or .

In some embodiments, ring B is C6-C10 aryl or 5- to 10-membered heteroaryl.

In some embodiments, ring B is C6-C10 aryl or 5- to 10-membered heteroaryl substituted with one or more R15.

In some embodiments, ring B is C6-C10 aryl or 5- to 10-membered heteroaryl tuted with one R15.

In some embodiments, ring B is C6-C10 aryl or 5- to 10-membered aryl substituted with two or more R15.

In some embodiments, is , , , , , , Attorney Docket No.: EPIZ-073/001WO (311622-2509) , , , , or .

In some embodiments, is R15 , , , , , , , , , or .

In some ments, the compounds of Formula (I0) include those of any of Formulae (I0a)-(I0l): (I0a), (I0b), (I0c), (I0d), Attorney Docket No.: EPIZ-073/001WO (311622-2509) (I0e), (I0f), (I0g), (I0h), (I0i), (I0j), (I0k), (I0l), and tautomers thereof, and pharmaceutically acceptable salts of the nds and the tautomers.

In some embodiments, the compounds of Formula (I0) include those of any of Formulae (I0a’)-(I0i’): (I0a’), (I0b’), (I0c’), (I0d’), Attorney Docket No.: EPIZ-073/001WO 2-2509) (I0e’), (I0f’), (I0g’), (I0h’), (I0i’), and tautomers thereof, and pharmaceutically acceptable salts of the compounds and the tautomers.

In some embodiments, R1 is C1-C4 alkyl. In some embodiments, R1 is methyl. In some embodiments, R1 is H.

In some embodiments, R3 is C1-C6 alkyl. In some embodiments, R3 is methyl. In some embodiments, R3 is H.

In some ments, R5 is C1-C6 alkyl. In some embodiments, R5 is methyl.

In some embodiments, R8 is C1-C6 alkyl. In some embodiments, R8 is methyl. In some ments, R8 is H.

In some embodiments, R9 is –Q4-T4, in which Q4 is C1-C6 alkylene, and T4 is H. In some time, R9 is methyl.

In some ments, R7 is –Q2-T2, in which Q2 is a bond or C(O)NRe, and T2 is 5- to 10- membered heteroaryl or 4- to 12-membered heterocycloalkyl, wherein the 5- to 10-membered heteroaryl or 4- to 12-membered cycloalkyl is optionally substituted with one or more –Q3- In some embodiments, R7 is –Q2-T2, in which Q2 is a bond, and T2 is 5- to 10-membered aryl or 4- to 12-membered heterocycloalkyl, wherein the 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more –Q3-T3.

Attorney Docket No.: EPIZ-073/001WO (311622-2509) In some embodiments, R7 is –Q2-T2, in which Q2 is a bond, and T2 is 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is optionally substituted with one or more – Q3-T3.

NH N In some embodiments, T2 is selected from , , , , N HN , , N , N , , , , , , S N , , , , N , , , , , , , , , and tautomers thereof, each of which is optionally tuted with one or more –Q3-T3.

In some embodiments, T2 is ed from , , , and tautomers thereof, each of which is optionally tuted with one or more –Q3-T3.

In some embodiments, T2 is optionally substituted with one or more –Q3-T3.

In some embodiments, T2 is or .

In some embodiments, T2 is ally substituted with one or more –Q3-T3.

In some embodiments, T2 is , , or .

In some embodiments, T2 is optionally substituted with one or more –Q3-T3.

Attorney Docket No.: 73/001WO (311622-2509) In some ments, T2 is , , or .

In some embodiments, each Q3 independently is a C1-C3 ne linker, and each T3 independently is selected from the group consisting of ORf, C(O)Rf, C(O)ORf, OC(O)Rf, S(O)2Rf, NRfRg, OC(O)NRfRg, NRfC(O)ORg, fRg, and NRfC(O)Rg, each of Rf and Rg independently being H, C3-C8 cycloalkyl, or C1-C6 alkyl optionally tuted with C3-C8 cycloalkyl, in which the C3-C8 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl or 5- to 6-membered heteroaryl is optionally substituted with one or more halo, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy.

In some embodiments, each Q3 independently is a C1-C3 alkylene linker, and each T3 independently is NRfRg, each of Rf and Rg independently being H, C3-C8 cycloalkyl, or C1-C6 alkyl ally substituted with C3-C8 cycloalkyl, in which the C3-C8 cycloalkyl, C6-C10 aryl, 4- to 7-membered cycloalkyl or 5- to 6-membered heteroaryl is optionally substituted with one or more halo, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 .

In some embodiments, each Q3 independently is a C1-C3 alkylene linker, and each T3 independently is NRfRg, each of Rf and Rg independently being H or C1-C6 alkyl.

In some embodiments, each Q3 independently is a C1-C3 alkylene linker, and each T3 independently is NRfRg, each of Rf and Rg independently being H or methyl.

In some embodiments, each Q3 independently is a C1-C3 alkylene linker, and each T3 independently is NHCH3.

In some embodiments, each Q3 independently is methylene, and each T3 independently is NHCH3.

In some embodiments, R7 is , , , N N NH NH N N H , , , H , or .

In some embodiments, R14 is H, halo, or –OR6.

In some embodiments, R14 is halo or –OR6.

In some embodiments, R14 is H.

Attorney Docket No.: EPIZ-073/001WO (311622-2509) In some embodiments, R14 is halo. In some embodiments, R14 is F. In some embodiments, R14 is Cl. In some ments, R14 is Br. In some embodiments, R14 is I.

In some embodiments, R14 is –OR6. In some embodiments, R6 is –Q1-T1, in which Q1 is a C1-C6 alkylene linker, and T1 is H. In some embodiments, R6 is –Q1-T1, in which Q1 is methylene, and T1 is H. In some embodiments, R14 is -OCH3.

In some embodiments, R15 is H or halo.

In some embodiments, R15 is H.

In some embodiments, R15 is halo. In some embodiments, R15 is F. In some embodiments, R15 is Cl. In some embodiments, R15 is Br. In some embodiments, R15 is I.

In some embodiments, R14 is halo or –OR6, and R15 is H or halo.

In some embodiments, R14 is halo, and R15 is H. In some embodiments, R14 is F, and R15 is H. In some embodiments, R14 is Cl, and R15 is H. In some embodiments, R14 is Br, and R15 is H. In some ments, R14 is I, and R15 is H.

In some embodiments, R14 is–OR6, and R15 is H. In some embodiments, R14 is -OCH3, and R15 is H.

In some embodiments, R14 is halo, and R15 is halo. In some embodiments, R14 is F, and R15 is F. In some embodiments, R14 is Cl, and R15 is F. In some embodiments, R14 is Br, and R15 is F. In some ments, R14 is I, and R15 is F. In some embodiments, R14 is F, and R15 is Cl.

In some embodiments, R14 is Cl, and R15 is Cl. In some embodiments, R14 is Br, and R15 is Cl. In some embodiments, R14 is I, and R15 is Cl. In some ments, R14 is F, and R15 is Br. In some embodiments, R14 is Cl, and R15 is Br. In some ments, R14 is Br, and R15 is Br. In some embodiments, R14 is I, and R15 is Br. In some embodiments, R14 is F, and R15 is I. In some embodiments, R14 is Cl, and R15 is I. In some embodiments, R14 is Br, and R15 is I. In some embodiments, R14 is I, and R15 is I.

In some embodiments, R14 is –OR6, and R15 is halo. In some embodiments, R14 is -OCH3, and R15 is halo. In some embodiments, R14 is -OCH3, and R15 is F. In some embodiments, R14 is - OCH3, and R15 is Cl. In some embodiments, R14 is -OCH3, and R15 is Br. In some embodiments, R14 is -OCH3, and R15 is I.

In some embodiments, the compound is of Formula (I), or a er thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.

In some embodiments, ring B is phenyl or 6-membered heteroaryl (e.g., pyridyl or pyrimidyl).

Attorney Docket No.: EPIZ-073/001WO (311622-2509) In some embodiments, is , , , OR6 N OR6 N OR6 , R7 , , R7 , R7 , OR6 OR6 R7 , N R7 , or .

In some embodiments, ring B is phenyl or 6-membered heteroaryl (e.g., pyridyl or pyrimidyl) optionally substituted with one or more R15.

In some embodiments, ring B is phenyl or 6-membered heteroaryl (e.g., pyridyl or pyrimidyl) ally substituted with one R15.

In some embodiments, is , R15 , , , , , , , , or .

In some embodiments, the compounds of Formula (I) include those of any of ae (Ia)-(Il): Attorney Docket No.: EPIZ-073/001WO (311622-2509) (Ia), (Ib), (Ic), (Id), R4 OR6 R4 N N R8 R8 N N N R7 N N N N R7 R9 R1 (Ie), R9 R1 (If), R4 OR6 N N N N N R7 R9 R1 (Ig), (Ih), N N N N R7 R9 R2 R1 (Ii), (Ij), (Ik), (Il), and tautomers f, and pharmaceutically acceptable salts of the compounds or the tautomers.

In some embodiments, the compounds of Formula (I) include those of any of Formulae (Ia’)-(Ii’): Attorney Docket No.: EPIZ-073/001WO (311622-2509) (Ia’), (Ib’), (Ic’), (Id’), (Ie’), (If’), (Ig’), (Ih’), (Ii’), and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers.

In some embodiments, the compound is of Formula (II0) or a tautomer thereof, or a pharmaceutically acceptable salt of the nd or the tautomer.

In some embodiments, the compounds of Formula (II0) e those of any of Formulae (II0a) and (II0b): Attorney Docket No.: EPIZ-073/001WO (311622-2509) (II0a), (II0b), and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers.

In some embodiments, the compound is of Formula (II) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.

In some embodiments, the compound is of Formula (II) include those of any of Formulae (IIa) and (IIb): (II0a), (II0b), and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the tautomers.

In some embodiments, the nd is of Formula (III0) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.

In some ments, the compounds of a (III0) include those of any of Formulae (III0a) and (III0b): (III0a), (III0b), and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the ers.

In some embodiments, the compound is of Formula (III) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the er.

In some embodiments, the compound is of Formula (IV0) or a tautomer thereof, or a ceutically acceptable salt of the compound or the tautomer.

Attorney Docket No.: EPIZ-073/001WO (311622-2509) In some embodiments, the compounds of Formula (IV0) include those of Formulae (IV0a) and (IV0b): (IV0a), (IV0b), and tautomers thereof, and pharmaceutically acceptable salts of the compounds or the ers.

In some embodiments, at most one of R3 and R5 is not H.

In some embodiments, at least one of R3 and R5 is not H.

In some embodiments, R3 is H or halo.

In some embodiments, at most one of R4 and R5 is not H.

In some embodiments, at least one of R4 and R5 is not H.

In some embodiments, R4 is H, C1-C6 alkyl, or halo.

In some ments, at most one of R2 and R5 is not H.

In some embodiments, at least one of R2 and R5 is not H.

In some embodiments, R2 is H, C1-C6 alkyl, or halo.

In some ments, R5 is C1-C6 alkyl optionally substituted with one or more of halo, hydroxyl, or C1-C6 alkoxyl. In some embodiments, R5 is unsubstituted C1-C6 alkyl (e.g., methyl or ethyl).

In some embodiments, each of X5, X6 and X7 is CH.

In some ments, at least one of X5, X6 and X7 is N.

In some embodiments, at most one of X5, X6 and X7 is N.

In some embodiments, R10 is optionally substituted 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, olidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, ydro-2H-pyranyl, 3,6- dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, morpholinyl, etc.). In some embodiments, R10 is optionally substituted with one or more halo, cyano, hydroxyl, oxo, amino, mono- or di- mino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C(O)NRjRk, or NRjC(O)Rk.

Attorney Docket No.: EPIZ-073/001WO (311622-2509) In some ments, R10 is connected to the bicyclic group of Formula (II) via a carboncarbon bond. In some embodiments, R10 is connected to the bicyclic group of Formula (II) via a -nitrogen bond.

In some embodiments, R10 is halo.

In some embodiments, R10 is optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, e.g., optionally substituted with one or more halo, cyano, hydroxyl, oxo, amino, mono- or di- alkylamino, C1-C6 alkoxy, C(O)NRjRk, or NRjC(O)Rk.

In some embodiments, R10 is C3-C8 cycloalkyl optionally substituted with one or more halo, cyano, hydroxyl, oxo, amino, mono- or di- alkylamino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 , C(O)NRjRk, or NRjC(O)Rk.

In some embodiments, R10 is C3-C8 cycloalkyl optionally substituted with C(O)NRjRk or NRjC(O)Rk.

In some ments, R11 and R12 together with the carbon atom to which they are attached form a 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6- tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, ydro-2H- thiopyranyl, 1,4-diazepanyl, azepanyl, morpholinyl, etc.), n the 4- to 7-membered heterocycloalkyl is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, oxo, amino, mono- or di- alkylamino, or C1-C6 alkoxyl.

In some embodiments, R11 and R12 together with the carbon atom to which they are attached form an unsubstituted 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S (e.g., azetidinyl, oxetanyl, thietanyl, idinyl, olidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6- tetrahydropyridinyl, zinyl, tetrahydro-2H-pyranyl, hydro-2H-pyranyl, tetrahydro-2H- thiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, morpholinyl, etc.).

In some embodiments, R11 and R12 together with the carbon atom to which they are attached form a C4-C8 cycloalkyl which is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, oxo, amino, mono- or di- alkylamino, or C1-C6 alkoxyl.

In some embodiments, R11 and R12 together with the carbon atom to which they are attached form an unsubstituted C4-C8 cycloalkyl.

In some embodiments, each of X5 and X6 is CH.

Attorney Docket No.: EPIZ-073/001WO (311622-2509) In some embodiments, each of X5 and X6 is N.

In some embodiments, one of X5 and X6 is CH and the other is CH.

In some embodiments, R6 is –Q1-T1, in which Q1 is a bond or C1-C6 alkylene linker optionally substituted with one or more of halo, and T1 is H, halo, cyano, or RS1, in which RS1 is C3-C8 cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl ning 1-4 atoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and RS1 is optionally substituted with one or more of halo, C1-C6 alkyl, C2-C6 l, C2-C6 alkynyl, hydroxyl, oxo, NRcRd, or C1-C6 alkoxyl.

In some embodiments, R6 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, each optionally substituted with one or more of halo, cyano, yl, or C1-C6 alkoxyl.

In some embodiments, R6 is unsubstituted C1-C6 alkyl (e.g., methyl).

In some embodiments, R7 is –Q2-T2, in which Q2 is a bond or C(O)NRe, and T2 is 5- to 10- membered heteroaryl or 4- to 12-membered heterocycloalkyl, wherein the 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more –Q3- In some embodiments, Q2 is a bond.

In some embodiments, Q2 is CONH or NHCO.

In some embodiments, T2 is 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S (e.g., a 4 to 7-membered monocyclic heterocycloalkyl or 7 to 12-membered bicyclic cycloalkyl such as azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, idinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H- pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, azepanyl, 2-oxa azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxaazaspiro[3.3]heptanyl, 2,6- diazaspiro[3.3]heptanyl, morpholinyl, 3-azabicyclo[3.1.0]hexanyl, icyclo[3.1.0]hexanyl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7- tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2- azaspiro[3.3]heptanyl, 2-methylazaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methylazaspiro[4.5]decanyl, 2-oxaazaspiro ctanyl, azaspiro[3.4]octanyl, and the like), which is optionally substituted with one or more –Q3-T3.

Attorney Docket No.: EPIZ-073/001WO (311622-2509) In some embodiments, T2 is 8- to 12-membered bicyclic heterocycloalkyl that comprises a - or 6-membered aryl or heteroaryl ring fused with a non-aromatic ring. In some embodiments, the 5- or 6-membered aryl or heteroaryl ring is ted to Q2.

In some embodiments, T2 is 5- to 10-membered heteroaryl.

In some embodiments, T2 is selected from , , , , N N , , , N , , , , , , , , , and tautomers thereof, each of which is optionally substituted with one or more –Q3-T3, wherein X8 is NH, O, or S, each of X9, X10, X11, and X12 is independently CH or N, and at least one of X9, X10, X11, and X12 is N, and ring A is a C5-C8 lkyl, phenyl, 6-membered heteroaryl, or 4- to 8-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S.

NH N In some embodiments, T2 is selected from , , , , N HN , , N , N , , , , , , S N , , , , N , , , , , , , , , , , , , ey Docket No.: EPIZ-073/001WO (311622-2509) , H , , , , , , N N N N , H H , H H , , , , , , , , , , , , , , , , , , , , H , , , , , , , , , , , , , , , , N N N NH NH N N N N , , , , H , H , , , , , , , HN N N HN N , , , , , , ey Docket No.: EPIZ-073/001WO (311622-2509) HN N , , , , , , , , , , , , , , , O , , , O N , , , , , , O N , , , , , , , , , , , , N N , , , , , , H H , HN N H , , , , , , N N O N N , , , , H , , , N N N O N , , H , , , , , ey Docket No.: EPIZ-073/001WO (311622-2509) , , , H , , , , H , , , , , , HN N N , , , , , , H H N N N N N N H , , , , , , , , , , , , , , , , , , , , , , , , , , , , N N N N , , , , , H , , N N N N N N , , H , H , , , , , , , , , ey Docket No.: EPIZ-073/001WO (311622-2509) , , , , , , N N N N , , , , , , , N N N O , O , , , , , , O N O N N , , , , , , , , , , , , , N N N N , N , N , , , , , N N N N N N N N H , H , , , , , , HN N , , , , , , N H N N N N , , , , N , N , , N O N , , , , O N , , , ey Docket No.: EPIZ-073/001WO (311622-2509) , , , , , , , O O , , , , , N , , N O O N , , , , H , , , , H , , , , , , , , , , , H H N N N N N N O O N N O N , , , , , , , , , N , , , , , N N H , , , , , , , , , , , , N N H N N N N N N , , N , N , , , , Attorney Docket No.: 73/001WO (311622-2509) , , , , , , , , , , , , , , , , N , , , , , N N N N N N N N H , H , , , , , , , , , , , N N N N , N , , N , , , , N O N N N N N O N N , O N , , , , , , , , , , , , , H , N N , , , , H , H , N N N N N N , , , , , H , H , Attorney Docket No.: 73/001WO (311622-2509) N N N N , , , , , H , H , N N N N , , , , , H , H , , , H , , , N , H , , , , , , , , , , , , , , , , , , , N N , , , , , , , , , , , , N N , , , , , , N N N N N , H , , , , , , ey Docket No.: EPIZ-073/001WO (311622-2509) N N , H , , , , , , N N H , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , N N N N , , , , N , , , , , , , , , , , , , , , , , N N , , , N , N , , , N N N , , N N , , , , , Attorney Docket No.: 73/001WO (311622-2509) , , , , , , , , , , N , , , , N O , , , , , , , N N N O O , , , , , , , N N , , , , , , , , , , N , , , , , , , , , , , , , , , , , , N N N N , , , , N , , , N N N N N , , N N , , , , , , , , , , , , Attorney Docket No.: EPIZ-073/001WO (311622-2509) , , , N , , , , , , , , , , , , , , N N , , , , , O , H O N N N NH2 O NH2 NH N N N N N N N N O , H , H , H , H , , Cl , and tautomers thereof, each of which is ally substituted with one or more – Q3-T3.

In some embodiments, T2 is selected from , , , , , , , , , , , , , , , , , , HN , Attorney Docket No.: EPIZ-073/001WO (311622-2509) H H N HN N N N HN HN N N N N , , , , O , , O N N HN N , , , , H , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and tautomers thereof, each of which is optionally substituted with one or more –Q3-T3.

In some embodiments, each Q3 independently is a bond or C1-C3 alkylene linker each optionally tuted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy.

In some ments, each T3 independently is ed from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, 4- to 7-membered heterocycloalkyl, ORf, C(O)Rf, C(O)ORf, NRfRg, C(O)NRfRg, and NRfC(O)Rg, in which the C3-C8 cycloalkyl or 4- to 7-membered heterocycloalkyl is optionally substituted with one or more halo, cyano, hydroxyl, C1-C6 alkyl or C1-C6 alkoxy.

In some embodiments, –Q3-T3 is oxo.

In some embodiments, each T3 ndently is NRfRg, C(O)NRfRg, or NRfC(O)Rg. In some embodiments, each of Rf and Rg is H. In some embodiments, each of Rf and Rg Attorney Docket No.: EPIZ-073/001WO 2-2509) independently is H, C3-C8 cycloalkyl, or C1-C6 alkyl optionally substituted with C3-C8 cycloalkyl.

In some embodiments, one of Rf and Rg is H and the other is C1-C6 alkyl optionally substituted with C3-C8 cycloalkyl. In some embodiments, one of Rf and Rg is H and the other is C3-C8 cycloalkyl. In some embodiments, one of Rf and Rg is C1-C6 alkyl and the other is C3-C8 cycloalkyl.

In some ments, at least one of R8 and R9 is H.

In some embodiments, each of R8 and R9 is H.

In some embodiments, R8 is H.

In some embodiments, R9 is –Q4-T4, in which Q4 is a bond or C1-C6 alkylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T4 is H, halo, ORh, NRhRi, )Ri, C(O)NRhRi, C(O)Rh, C(O)ORh, or RS2, in which RS2 is C3-C8 cycloalkyl or 4- to 7-membered heterocycloalkyl, and RS2 is optionally substituted with one or more –Q5-T5.

In some embodiments, each Q5 independently is a bond or C1-C3 alkylene linker.

In some ments, each T5 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, ORj, C(O)Rj, C(O)ORj, NRjRk, C(O)NRjRk, and NRjC(O)Rk.

In some embodiments, R9 is C1-C3 alkyl.

For a compound of any one of formulae (I0)-(IV0), II), (I0a)-(I0l), (I0a’)-(I0i’), (Ia)- (Il), (Ia’)-(Ii’), (II0a)-(II0b), (III0a)-(III0b), and (IV0a)-(IV0b), X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, ring B, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rk, Rl, and Rm can each be, where applicable, selected from any of the groups described herein, and any group described herein for any of X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, ring B, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rk, Rl, and Rm can be combined, where applicable, with any group described herein for one or more of the remainder of X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, ring B, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rk, Rl, and Rm.

In some embodiments, the compound is selected from those in Table 1, tautomers thereof, and pharmaceutically acceptable salts of the compounds and tautomers.

In some embodiments, one or more of the compounds disclosed herein (e.g., a compound of any of ae (I0)-(IV0) and a (I)-(III)) inhibit a kinase with an enzyme Attorney Docket No.: EPIZ-073/001WO (311622-2509) inhibition IC50 value of about 100 nM or greater, 1 µM or greater, 10 µM or r, 100 µM or r, or 1000 µM or greater.

In some embodiments, one or more of the nds disclosed herein (e.g., a compound of any of Formulae (I0)-(IV0) and Formula (I)-(III)) inhibit a kinase with an enzyme inhibition IC50 value of about 1 mM or r.

In some embodiments, one or more of the compounds disclosed herein (e.g., a compound of any of Formulae IV0) and Formula (I)-(III)) inhibit a kinase with an enzyme inhibition IC50 value of 1 µM or greater, 2 µM or greater, 5 µM or r, or 10 µM or greater, wherein the kinase is one or more of the following: AbI, AurA, CHK1, MAP4K, IRAK4, JAK3, EphA2, FGFR3, KDR, Lck, MARK1, MNK2, PKCb2, SIK, and Src.

The present disclosure provides a ceutical composition comprising a nd of any one of the Formulae described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The present disclosure provides a method of preventing or treating a blood disorder via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, e.g., any of Formulae (I0)-(IV0) and Formulae (I)-(III).

The present disclosure es a method of preventing or treating cancer (e.g., via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2), the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, e.g., any of Formulae (I0)-(IV0) and Formulae (I)-(III).

In some embodiments, the blood er is sickle cell anemia or β-thalassemia.

In some embodiments, the blood disorder is a hematological cancer.

In some embodiments, the cancer is lymphoma, leukemia, melanoma, breast cancer, ovarian cancer, hepatocellular carcinoma, prostate carcinoma, lung cancer, brain cancer, or logical cancer.

In some embodiments, the hematological cancer is acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL).

In some embodiments, one or more of the compounds sed herein (e.g., a compound of any of Formulae (I0)-(IV0) and Formula (I)-(III)) are selective inhibitors of EHMT2.

Representative compounds of the t disclosure include compounds listed in Table 1 or tautomers and salts thereof. ey Docket No.: EPIZ-073/001WO (311622-2509) Table 1 Compound Structure N N N N N Attorney Docket No.: 73/001WO (311622-2509) Compound Structure ey Docket No.: EPIZ-073/001WO (311622-2509) Compound Structure Attorney Docket No.: EPIZ-073/001WO 2-2509) Compound Structure Attorney Docket No.: 73/001WO (311622-2509) Compound Structure Attorney Docket No.: EPIZ-073/001WO 2-2509) Compound Structure 41 N N N N ey Docket No.: EPIZ-073/001WO (311622-2509) Compound Structure O N 45 N N N N N ey Docket No.: EPIZ-073/001WO (311622-2509) Compound Structure Attorney Docket No.: EPIZ-073/001WO 2-2509) Compound Structure Attorney Docket No.: 73/001WO (311622-2509) Compound Structure Attorney Docket No.: EPIZ-073/001WO 2-2509) Compound Structure ey Docket No.: EPIZ-073/001WO (311622-2509) Compound Structure Attorney Docket No.: 73/001WO (311622-2509) Compound Structure N N N N O H H N N N N N N N O H H N N N 89 N N NH2 ey Docket No.: EPIZ-073/001WO (311622-2509) Compound Structure 91 N N NH2 O HN 94 N H N Attorney Docket No.: EPIZ-073/001WO (311622-2509) Structure O HN 96 N 99 N Attorney Docket No.: EPIZ-073/001WO 2-2509) Compound Structure Attorney Docket No.: EPIZ-073/001WO 2-2509) Compound Structure 107 N N Attorney Docket No.: EPIZ-073/001WO 2-2509) Compound Structure N N 110 N N ey Docket No.: EPIZ-073/001WO (311622-2509) Compound Structure Attorney Docket No.: EPIZ-073/001WO (311622-2509) Structure 120 N N N N Attorney Docket No.: 73/001WO (311622-2509) Compound Structure 125 NH N N N Attorney Docket No.: 73/001WO (311622-2509) Compound Structure Attorney Docket No.: 73/001WO (311622-2509) Compound Structure ey Docket No.: EPIZ-073/001WO (311622-2509) Compound Structure 135 O N N N N H H N N N N H H N N N Attorney Docket No.: EPIZ-073/001WO 2-2509) Compound Structure N N N H H N ey Docket No.: EPIZ-073/001WO (311622-2509) Compound Structure 143 N Attorney Docket No.: EPIZ-073/001WO 2-2509) Compound Structure Attorney Docket No.: EPIZ-073/001WO (311622-2509) Structure 151 N N Attorney Docket No.: EPIZ-073/001WO (311622-2509) Structure N N ey Docket No.: EPIZ-073/001WO (311622-2509) Compound Structure Attorney Docket No.: EPIZ-073/001WO 2-2509) Compound Structure H F 165 NH ey Docket No.: EPIZ-073/001WO (311622-2509) Compound Structure Attorney Docket No.: 73/001WO (311622-2509) Compound Structure 174 N N N N H H N N N N N H H Attorney Docket No.: 73/001WO (311622-2509) Compound Structure Attorney Docket No.: EPIZ-073/001WO (311622-2509) Structure ey Docket No.: EPIZ-073/001WO (311622-2509) Compound Structure N N N N N 193 NH2 N N N N N 194 NH2 Attorney Docket No.: EPIZ-073/001WO (311622-2509) Structure N N N N N 195 NH2 Attorney Docket No.: EPIZ-073/001WO (311622-2509) Structure 199 N F HN Attorney Docket No.: EPIZ-073/001WO (311622-2509) Structure N N 204 N ey Docket No.: EPIZ-073/001WO (311622-2509) Compound Structure N N N N H H N N N Attorney Docket No.: EPIZ-073/001WO 2-2509) Compound Structure Attorney Docket No.: EPIZ-073/001WO 2-2509) Compound Structure Attorney Docket No.: EPIZ-073/001WO (311622-2509) Structure Attorney Docket No.: EPIZ-073/001WO 2-2509) Compound Structure 229 N N N N H H N N N H H N N ey Docket No.: EPIZ-073/001WO (311622-2509) Compound Structure Attorney Docket No.: EPIZ-073/001WO (311622-2509) Structure Attorney Docket No.: 73/001WO (311622-2509) Compound Structure O N H H N N N 245 N ey Docket No.: EPIZ-073/001WO (311622-2509) Compound Structure H H N N N 250 N Attorney Docket No.: EPIZ-073/001WO 2-2509) Compound Structure Attorney Docket No.: EPIZ-073/001WO (311622-2509) Structure O N H H N N N N N 259 H Attorney Docket No.: EPIZ-073/001WO (311622-2509) Structure 276 N N N N H H O N Attorney Docket No.: EPIZ-073/001WO 2-2509) Compound Structure 282 N ey Docket No.: EPIZ-073/001WO (311622-2509) Compound Structure Attorney Docket No.: 73/001WO (311622-2509) Compound Structure Attorney Docket No.: EPIZ-073/001WO (311622-2509) Structure Attorney Docket No.: EPIZ-073/001WO 2-2509) Compound Structure Attorney Docket No.: EPIZ-073/001WO 2-2509) Compound Structure Attorney Docket No.: EPIZ-073/001WO (311622-2509) Structure 309 O HN N N ey Docket No.: EPIZ-073/001WO (311622-2509) Compound Structure Attorney Docket No.: EPIZ-073/001WO (311622-2509) Structure Attorney Docket No.: EPIZ-073/001WO 2-2509) Compound Structure Attorney Docket No.: EPIZ-073/001WO 2-2509) Compound Structure ey Docket No.: EPIZ-073/001WO (311622-2509) Compound Structure 338 HN N N 340 N N HN Attorney Docket No.: EPIZ-073/001WO (311622-2509) Structure NH N F 345 NH Attorney Docket No.: EPIZ-073/001WO (311622-2509) Structure ey Docket No.: EPIZ-073/001WO (311622-2509) Compound Structure Attorney Docket No.: 73/001WO (311622-2509) Compound Structure Attorney Docket No.: EPIZ-073/001WO 2-2509) Compound Structure NH N F 366 NH NH N 367 NH Attorney Docket No.: EPIZ-073/001WO 2-2509) Compound Structure Attorney Docket No.: EPIZ-073/001WO (311622-2509) Structure NH N Cl 374 NH NH N Cl 381 NH Attorney Docket No.: 73/001WO (311622-2509) Compound Structure Attorney Docket No.: EPIZ-073/001WO (311622-2509) Compound Structure As used herein, "alkyl", "C1, C2, C3, C4, C5 or C6 alkyl" or "C1-C 6 alkyl" is intended to include C1, C2, C3, C4, C5 or C6 ht chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5 or C6 branched saturated aliphatic arbon groups. In some embodiments, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5 and C6 alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not d to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl or n-hexyl.

Attorney Docket No.: EPIZ-073/001WO (311622-2509) In certain embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C1-C6 for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or ed alkyl has four or fewer carbon atoms.

As used herein, the term "cycloalkyl" refers to a saturated or unsaturated nonaromatic hydrocarbon mono- or multi-ring (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, utyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. The term "heterocycloalkyl" refers to a saturated or unsaturated nonaromatic 3-8 membered monocyclic, 7- 12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered lic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g.¸ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless ied otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, idinyl, dioxanyl, tetrahydrofuranyl, olinyl, nyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, linyl, tetrahydrothiopyranyl, 1,4-diazepanyl, azepanyl, 2-oxaazabicyclo[2.2.1]heptanyl, 2,5- diazabicyclo[2.2.1]heptanyl, 2-oxaazaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4- dioxaazaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, piro[4.5]decanyl, 1- azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1,5'- furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3- azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 1,4,5,6-tetrahydropyrrolo[3,4- c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4- c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methylazaspiro[3.5]nonanyl, 2- azaspiro[4.5]decanyl, 2-methylazaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxaazaspiro ctanyl, and the like. In the case of multicyclic non-aromatic rings, only one of the rings needs to be non-aromatic (e.g., 1,2,3,4-tetrahydronaphthalenyl or 2,3-dihydroindole).

The term "optionally substituted alkyl" refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the arbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, Attorney Docket No.: EPIZ-073/001WO (311622-2509) halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, ylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, inato, amino (including mino, dialkylamino, arylamino, diarylamino and rylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, ryl, or an aromatic or heteroaromatic moiety.

As used herein, "alkyl linker" or "alkylene linker" is ed to include C1, C2, C3, C4, C5 or C6 ht chain (linear) saturated divalent aliphatic hydrocarbon groups and C3, C4, C5 or C6 branched saturated aliphatic hydrocarbon groups. In some embodiments, C1-C6 alkylene linker is intended to include C1, C2, C3, C4, C5 and C6 alkylene linker groups. Examples of alkylene linker include, moieties having from one to six carbon atoms, such as, but not limited to, methyl (-CH2-), ethyl (-CH2CH2-), n-propyl (-CH2CH2CH2-), i-propyl 3CH2-), l (-CH2CH2CH2CH2- ), s-butyl (-CHCH3CH2CH2-), i-butyl (-C(CH3) 2CH2-), n-pentyl (-CH2CH2CH2CH2CH2-), yl (-CHCH3CH2CH2CH2-) or l (-CH2CH2CH2CH2CH2CH2-).

"Alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls bed above, but that contain at least one double bond. In some embodiments, the term "alkenyl" includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and ed alkenyl groups.

In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes l groups containing two to six carbon atoms. The term "C3-C6" includes alkenyl groups containing three to six carbon atoms.

The term "optionally substituted alkenyl" refers to unsubstituted alkenyl or alkenyl having designated tuents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for e, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, ycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ), amidino, imino, Attorney Docket No.: EPIZ-073/001WO (311622-2509) sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

"Alkynyl" includes rated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. In some embodiments, "alkynyl" includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain ments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" es alkynyl groups containing two to six carbon atoms. The term "C3-C6" includes alkynyl groups containing three to six carbon atoms. As used herein, "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to e C2, C3, C4, C5 or C6 chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. In some embodiments, C2-C6 alkenylene linker is intended to include C2, C3, C4, C5 and C6 alkenylene linker groups.

The term "optionally tuted alkynyl" refers to unsubstituted l or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such tuents can include, for example, alkyl, alkenyl, l, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, arbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, amino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, oyl and ureido), amidino, imino, sulfhydryl, alkylthio, io, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or aromatic moiety.

Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) e both the unsubstituted moieties and the moieties having one or more of the designated substituents. In some ments, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6- tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

Attorney Docket No.: EPIZ-073/001WO (311622-2509) "Aryl" includes groups with aromaticity, including "conjugated," or multicyclic systems with one or more aromatic rings and do not contain any atom in the ring structure.

Examples include phenyl, naphthalenyl, etc.

"Heteroaryl" groups are aryl groups, as defined above, except having from one to four heteroatoms in the ring ure, and may also be referred to as "aryl heterocycles" or "heteroaromatics." As used herein, the term "heteroaryl" is intended to include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g.¸ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and . The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)p, where p = 1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.

Furthermore, the terms "aryl" and oaryl" include yclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring ons (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for e, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, laminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, rbonyl, lcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, lamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, rbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, hio, arylthio, thiocarboxylate, es, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, ryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic Attorney Docket No.: EPIZ-073/001WO 2-2509) rings, which are not aromatic so as to form a multicyclic system (e.g., in, methylenedioxyphenyl such as benzo[d][1,3]dioxoleyl).

As used herein, "carbocycle" or "carbocyclic ring" is intended to include any stable monocyclic, bicyclic or tricyclic ring having the specified number of carbons, any of which may be saturated, unsaturated, or aromatic. Carbocycle includes cycloalkyl and aryl. In some embodiments, a C3-C14 carbocycle is intended to include a monocyclic, bicyclic or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms. Examples of carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl, indanyl, adamantyl and tetrahydronaphthyl. d rings are also included in the definition of carbocycle, including, for example, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, and [4.4.0] bicyclodecane and [2.2.2] bicyclooctane. A bridged ring occurs when one or more carbon atoms link two jacent carbon atoms. In one embodiment, bridge rings are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge. Fused (e.g., naphthyl, tetrahydronaphthyl) and spiro rings are also included.

As used herein, "heterocycle" or "heterocyclic group" es any ring ure (saturated, unsaturated, or aromatic) which contains at least one ring heteroatom (e.g., 1-4 heteroatoms selected from N, O and S). Heterocycle includes heterocycloalkyl and heteroaryl.

Examples of cycles include, but are not limited to, morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazine, oxetane, pyran, ydropyran, azetidine, and tetrahydrofuran.

Examples of heterocyclic groups include, but are not limited to, acridinyl, yl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, azolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, oxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, azolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, olyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl (e.g., benzo[d][1,3]dioxoleyl), morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5- oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazol5(4H)-one, idinyl, yl, oxindolyl, Attorney Docket No.: EPIZ-073/001WO 2-2509) pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, nyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, dinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, inyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H- 1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

The term "substituted," as used , means that any one or more hydrogen atoms on the designated atom is replaced with a ion from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). e nd" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and ation into an efficacious therapeutic agent.

The term "optionally substituted," as used herein, means not being substituted (e.g., none of the one or more hydrogen atoms on the designated variable is replaced with any other group) or being substituted (e.g., any one or more hydrogen atoms on the designated variable is ed with a selection from the indicated groups, provided that the designated atom’s normal y is not exceeded, and that the substitution results in a stable compound).

When a bond to a substituent is shown to cross a bond ting two atoms in a ring, then such tuent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, in some embodiments, if a group is shown to be substituted with 0-2 R Attorney Docket No.: EPIZ-073/001WO (311622-2509) moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and/or variables are permissible, but only if such ations result in stable compounds.

The term "hydroxy" or "hydroxyl" includes groups with an -OH or -O-.

As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo and iodo. The term "perhalogenated" generally refers to a moiety wherein all hydrogen atoms are replaced by halogen atoms. The term "haloalkyl" or "haloalkoxyl" refers to an alkyl or alkoxyl substituted with one or more halogen atoms.

The term nyl" includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom. Examples of moieties containing a carbonyl include, but are not limited to, des, ketones, carboxylic acids, amides, esters, anhydrides, etc.

The term "carboxyl" refers to –COOH or its C1-C6 alkyl ester.

"Acyl" includes moieties that contain the acyl radical (R-C(O)-) or a carbonyl group.

"Substituted acyl" includes acyl groups where one or more of the hydrogen atoms are replaced by, for example, alkyl groups, alkynyl groups, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, ycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and rylamino), acylamino ding alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, amido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. " includes moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include carboxy, naphthyl carboxy, etc.

"Alkoxyalkyl," "alkylaminoalkyl," and "thioalkoxyalkyl" e alkyl groups, as described above, wherein oxygen, nitrogen, or sulfur atoms replace one or more hydrocarbon backbone carbon atoms.

The term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups ntly linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, y, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy . The alkoxy groups can be tuted with groups such as alkenyl, alkynyl, halogen, hydroxyl, Attorney Docket No.: EPIZ-073/001WO (311622-2509) alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, onato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and rylamino), acylamino (including alkylcarbonylamino, rbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. es of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methoxy, dichloromethoxy and trichloromethoxy.

The term "ether" or "alkoxy" es nds or moieties which contain an oxygen bonded to two carbon atoms or heteroatoms. In some embodiments, the term es "alkoxyalkyl," which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to an alkyl group.

The term "ester" includes compounds or moieties which n a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group. The term "ester" includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.

The term "thioalkyl" includes compounds or moieties which contain an alkyl group connected with a sulfur atom. The thioalkyl groups can be substituted with groups such as alkyl, alkenyl, l, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, arbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, hio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties.

The term "thiocarbonyl" or arboxy" includes compounds and moieties which n a carbon connected with a double bond to a sulfur atom.

The term ther" includes moieties which contain a sulfur atom bonded to two carbon atoms or heteroatoms. Examples of thioethers include, but are not limited to alkthioalkyls, Attorney Docket No.: EPIZ-073/001WO (311622-2509) alkthioalkenyls, and alkthioalkynyls. The term "alkthioalkyls" include moieties with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group. Similarly, the term "alkthioalkenyls" refers to moieties wherein an alkyl, alkenyl or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkenyl group; and alkthioalkynyls" refers to moieties wherein an alkyl, alkenyl or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.

As used herein, "amine" or " refers to -NH2. "Alkylamino" includes groups of compounds wherein the nitrogen of -NH2 is bound to at least one alkyl group. Examples of alkylamino groups include amino, methylamino, ethylamino, phenethylamino, etc.

"Dialkylamino" includes groups n the nitrogen of -NH2 is bound to two alkyl .

Examples of dialkylamino groups include, but are not limited to, dimethylamino and diethylamino. "Arylamino" and "diarylamino" e groups wherein the nitrogen is bound to at least one or two aryl groups, respectively. "Aminoaryl" and "aminoaryloxy" refer to aryl and aryloxy substituted with amino. "Alkylarylamino," "alkylaminoaryl" or "arylaminoalkyl" refers to an amino group which is bound to at least one alkyl group and at least one aryl group.

"Alkaminoalkyl" refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group. "Acylamino" includes groups wherein nitrogen is bound to an acyl group. Examples of acylamino include, but are not limited to, alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.

The term "amide" or "aminocarboxy" includes compounds or moieties that n a nitrogen atom that is bound to the carbon of a carbonyl or a thiocarbonyl group. The term es "alkaminocarboxy" groups that include alkyl, alkenyl or alkynyl groups bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group. It also es "arylaminocarboxy" groups that include aryl or heteroaryl es bound to an amino group that is bound to the carbon of a carbonyl or thiocarbonyl group. The terms "alkylaminocarboxy", "alkenylaminocarboxy", "alkynylaminocarboxy" and "arylaminocarboxy" include moieties wherein alkyl, alkenyl, alkynyl and aryl moieties, tively, are bound to a nitrogen atom which is in turn bound to the carbon of a carbonyl group. Amides can be substituted with substituents such as straight chain alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl or heterocycle.

Substituents on amide groups may be r substituted.

Compounds of the present disclosure that contain nitrogens can be converted to N-oxides by treatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid ) and/or hydrogen Attorney Docket No.: EPIZ-073/001WO (311622-2509) peroxides) to afford other compounds of the present disclosure. Thus, all shown and claimed nitrogen-containing compounds are considered, when allowed by valency and structure, to include both the nd as shown and its N-oxide derivative (which can be designated as NO or N+- O-). Furthermore, in other instances, the nitrogens in the compounds of the present disclosure can be converted to oxy or N-alkoxy nds. In some embodiments, N-hydroxy nds can be prepared by oxidation of the parent amine by an oxidizing agent such as m-CPBA. All shown and d nitrogen-containing compounds are also considered, when allowed by valency and structure, to cover both the compound as shown and its N-hydroxy (i.e., N-OH) and N-alkoxy (i.e., N-OR, wherein R is substituted or unsubstituted C1-C 6 alkyl, C1- C6 alkenyl, C1-C6 alkynyl, 3membered carbocycle or 3membered heterocycle) derivatives.

In the present ication, the structural formula of the compound represents a certain isomer for convenience in some cases, but the present sure includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like, it being understood that not all isomers may have the same level of activity. In addition, a crystal polymorphism may be present for the nds represented by the formula.

It is noted that any crystal form, crystal form mixture, or anhydride or hydrate thereof is included in the scope of the present disclosure.

"Isomerism" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the ement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are termed "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture." A carbon atom bonded to four nonidentical tuents is termed a "chiral center." l isomer" means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a e of diastereomers, termed "diastereomeric mixture." When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center.

Absolute uration refers to the arrangement in space of the substituents ed to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, Attorney Docket No.: EPIZ-073/001WO (311622-2509) , 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

"Geometric isomer" means the diastereomers that owe their existence to hindered on about double bonds or a cycloalkyl linker (e.g., 1,3-cylcobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn- Ingold-Prelog rules.

It is to be understood that the compounds of the t disclosure may be depicted as different chiral isomers or geometric isomers. It should also be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any ic forms, it being understood that not all isomers may have the same level of activity.

Furthermore, the structures and other compounds discussed in this disclosure include all atropic isomers thereof, it being tood that not all atropic isomers may have the same level of activity. "Atropic isomers" are a type of stereoisomer in which the atoms of two s are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

"Tautomer" is one of two or more ural isomers that exist in equilibrium and is readily converted from one ic form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. ers exist as a e of a eric set in solution. In ons where tautomerization is possible, a al equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including ature, solvent and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism.

Of the various types of tautomerism that are possible, two are commonly observed. In nol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

Attorney Docket No.: EPIZ-073/001WO (311622-2509) Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim, imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and ne), imine-enamine and enamine-enamine. Examples of lactam-lactim erism are as shown below.

It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that n tautomers may have a higher level of activity than others.

The term "crystal polymorphs", "polymorphs" or "crystal forms" means crystal structures in which a compound (or a salt or solvate thereof) can crystallize in ent crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to te. Crystal polymorphs of the compounds can be prepared by crystallization under different conditions.

The compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively d group (e.g., amino) on a substituted e compound. Suitable anions e de, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, ate, , maleate, ate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., oroacetate). The term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted benzene compound. Suitable Attorney Docket No.: EPIZ-073/001WO (311622-2509) cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. The substituted benzene compounds also e those salts containing quaternary nitrogen atoms.

Additionally, the compounds of the present disclosure, for example, the salts of the nds, can exist in either ed or ated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc.

Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

"Solvate" means solvent addition forms that contain either stoichiometric or ichiometric amounts of solvent. Some nds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is l, the solvate formed is an alcoholate.

Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.

As used herein, the term g" refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the ement of one functional group by r onal group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.

As defined herein, the term "derivative" refers to compounds that have a common core structure, and are substituted with various groups as described herein. In some embodiments, all of the compounds represented by Formula (II) are substituted bi-heterocyclic compounds, and have Formula (II) as a common core.

The term "bioisostere" refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The ive of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. es of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonimides, tetrazoles, ates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

The present disclosure is intended to include all isotopes of atoms occurring in the present nds. Isotopes include those atoms having the same atomic number but different mass Attorney Docket No.: EPIZ-073/001WO (311622-2509) numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include C-13 and C-14.

As used herein, the expressions "one or more of A, B, or C," "one or more A, B, or C," "one or more of A, B, and C," "one or more A, B, and C," "selected from the group consisting of A, B, and C", "selected from A, B, and C", and the like are used interchangeably and all refer to a ion from a group consisting of A, B, and/or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.

The present disclosure provides methods for the synthesis of the compounds of any of the Formulae bed . The present disclosure also provides detailed methods for the synthesis of various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the Examples. hout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is rial so long as the invention remains operable.

Moreover, two or more steps or actions can be conducted simultaneously.

The synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore s substituted starting materials can be used. The processes generally e the desired final compound at or near the end of the overall s, although it may be desirable in n instances to further convert the compound to a pharmaceutically able salt thereof.

Compounds of the present disclosure can be ed in a variety of ways using cially available starting materials, compounds known in the literature, or from y prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. rd tic methods and procedures for the preparation of organic les and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not d to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic sis, 3rd edition, John Wiley & Sons: Attorney Docket No.: EPIZ-073/001WO (311622-2509) New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of ts for Organic sis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are ed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure.

Compounds of the present disclosure can be conveniently prepared by a variety of methods familiar to those skilled in the art. The compounds of this disclosure having any of the Formulae described herein may be prepared according to the procedures illustrated in Schemes 1-4 below, from cially available starting materials or starting materials which can be prepared using literature procedures. Certain variables (such as R6 and R7) in Schemes 1-4 are as defined in any Formula described herein, unless otherwise specified.

One of ordinary skill in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups.

One of ordinary skill in the art will recognize that certain groups may require protection from the reaction conditions via the use of ting . Protecting groups may also be used to differentiate r functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999.

Preferred ting groups include, but are not limited to: For a hydroxyl : TBS, benzyl, THP, Ac For carboxylic acids: benzyl ester, methyl ester, ethyl ester, allyl ester For amines: Cbz, BOC, DMB For diols: Ac (x2) TBS (x2), or when taken together acetonides For thiols: Ac For benzimidazoles: SEM, benzyl, PMB, DMB For aldehydes: di-alkyl s such as oxy acetal or diethyl acetyl.

In the reaction schemes described herein, multiple stereoisomers may be produced. When no particular stereoisomer is indicated, it is tood to mean all le stereoisomers that could be ed from the reaction. A person of ordinary skill in the art will recognize that the Attorney Docket No.: EPIZ-073/001WO 2-2509) reactions can be optimized to give one isomer entially, or new schemes may be devised to produce a single isomer. If mixtures are produced, techniques such as preparative thin layer chromatography, preparative HPLC, preparative chiral HPLC, or preparative SFC may be used to separate the s.

The following abbreviations are used throughout the specification and are defined below: ACN acetonitrile Ac acetyl AcOH acetic acid AlCl3 aluminum chloride BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) t-BuOK potassium xide tBuONa or t-BuONa sodium t-butoxide br broad BOC tert-butoxy carbonyl Cbz benzyloxy carbonyl CDCl3CHCl3 chloroform CH2Cl2 dichloromethane CH3CN acetonitrile CsCO3 cesium carbonate CH3NO3 nitromethane d doublet dd doublet of doublets dq t of quartets DCE 1,2 dichloroethane DCM dichloromethane Δ heat δ chemical shift DIEA N,N-diisopropylethylamine (Hunig's base) DMB 2,4 dimethoxy benzyl DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DMSO-d6 ated dimethyl sulfoxide ey Docket No.: EPIZ-073/001WO (311622-2509) EA or EtOAc Ethyl acetate ES electrospray Et3N triethylamine equiv equivalents g grams h hours H2O water HCl hydrogen chloride or hydrochloric acid HPLC High mance liquid chromatography Hz Hertz IPA isopropyl alcohol i-PrOH isopropyl alcohol J NMR coupling constant K2CO3 potassium carbonate HI potassium iodide KCN potassium cyanide LCMS or LC-MS Liquid chromatography mass spectrum M molar m multiplet mg milligram MHz megahertz mL milliliter mm millimeter mmol millimole mol mole [M+1] molecular ion plus one mass unit m/z mass/charge ratio m-CPBA meta-chloroperbenzoic acid MeCN Acetonitrile MeOH methanol MeI Methyl iodide min minutes Attorney Docket No.: EPIZ-073/001WO (311622-2509) µm micron MsCl Mesyl chloride MW microwave irradiation N normal Na2SO4 sodium sulfate NH3 ammonia NaBH(AcO)3 sodium triacetoxyborohydride NaI sodium iodide Na2SO4 sodium sulfate NH4Cl ammonium chloride NH4HCO3 ammonium bicarbonate nm nanometer NMP N-methylpyrrolidinone NMR Nuclear Magnetic Resonance )2 palladium (II) acetate Pd/C Palladium on carbon Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0) PMB para methoxybenzyl ppm parts per million POCl3 phosphoryl de prep-HPLC preparative High Performance Liquid Chromatography PTSA para-toluenesulfonic acid p-TsOH para-toluenesulfonic acid RT retention time rt room temperature s singlet t triplet t-BuXPhos 2-Di-tert-butylphosphino-2′, 4′, 6′-triisopropylbiphenyl TEA ylamine TFA oroacetic acid TfO triflate THP tetrahydropyran Attorney Docket No.: EPIZ-073/001WO (311622-2509) TsOH tosic acid UV ultraviolet Scheme 1 R1 HN R2 N O H N N B1 N N N I N N H H CuI, 140oC A1 C1 Scheme 1 shows the synthesis of N2-(4-methoxy(1H-pyrazolyl)phenyl)-N4,6- dimethylpyrimidine-2,4-diamine C1 following a general route. An aryl iodide such as N2-(3- iodomethoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine A1 or a like reagent is heated in an organic solvent (e.g., DMSO) with a copper salt (e.g., CuI) and a nitrogen-containing heterocycle (e.g., disubstituted pyrazole B1). The ing substituted aryl or heteroaryl analog C1 can be used in further elaboration such as alkylation and salt formation.

Scheme 2 Scheme 2 shows the synthesis of N2-(4-methoxy(1H-pyrazolyl)phenyl)-N4,6- dimethylpyrimidine-2,4-diamine C2 following an alternate general route. An aryl iodide such as N2-(3-iodomethoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine A2 or a like reagent is combined in an organic solvent (e.g., DMSO) with a copper salt (e.g., CuI), a mild base (e.g., K3PO4), a e ligand (e.g., )-N1,N2-dimethylcyclohexane-1,2-diamine B2-b) and a nitrogen-containing cycle (e.g., disubstituted pyrazole B2-a). The resulting substituted aryl or heteroaryl analog C2 can be used in further elaboration such as alkylation and salt formation.

Scheme 3 Attorney Docket No.: EPIZ-073/001WO (311622-2509) Scheme 3 shows the synthesis of N2-(4-substituted-phenyl)-N4,6-dimethylpyrimidine- amine C3 following a general route. An aryl halide such as N2-(3-iodomethoxyphenyl)- N4,6-dimethylpyrimidine-2,4-diamine A3 or a like reagent is combined in a mixture of an organic solvent (e.g., dioxane) and water with a palladium (II) compound (e.g., Pd(dppf)Cl2), a mild base (e.g., K2CO3), and an aryl or aryl boronate (e.g., B3) to yield a substituted aryl or heteroaryl analog C3.

Scheme 4 Scheme 4 depicts the synthesis of 2-(2-methoxynitrophenyl)-2H-pyrazolo compound C4 following a general route (X can be CH2 or NH or O). An aryl hydrazide such as hoxy- -nitrophenyl)hydrazine A4 or a like reagent is combined in an organic solvent (e.g., methanol) with an enamineodiketone (e.g., B4) in the presence of an acid (e.g., acetic acid) to yield a substituted aryl or heteroaryl intermediate C4 via a cyclocondensation reaction.

A person of ordinary skill in the art will recognize that in the above schemes the order of many of the steps are interchangeable.

Compounds of the t disclosure inhibit the histone transferase activity of G9a, also known as KMT1C (lysine methyltransferase 1C) or EHMT2 (euchromatic histone methyltransferase 2), or a mutant thereof and, accordingly, in one aspect of the disclosure, certain compounds sed herein are candidates for treating, or ting certain ions, diseases, and disorders in which EHMT2 plays a role. The present disclosure provides methods for treating conditions and diseases the course of which can be influenced by modulating the methylation Attorney Docket No.: EPIZ-073/001WO (311622-2509) status of histones or other proteins, wherein said methylation status is mediated at least in part by the activity of EHMT2. Modulation of the methylation status of histones can in turn influence the level of expression of target genes ted by methylation, and/or target genes suppressed by methylation. The method includes administering to a subject in need of such ent, a therapeutically effective amount of a compound of the present disclosure, or a ceutically acceptable salt, polymorph, solvate, or stereoisomer thereof.

Unless ise stated, any description of a method of treatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to prepare a medicament to treat or prevent such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models.

In still another aspect, this disclosure relates to a method of modulating the activity of EHMT2, which catalyzes the dimethylation of lysine 9 on histone H3 (H3K9) in a subject in need thereof. In some embodiments, the method comprises the step of administering to a subject having a cancer sing a mutant EHMT2 a therapeutically effective amount of a compound described herein, wherein the nd(s) inhibits histone methyltransferase activity of EHMT2, thereby treating the cancer.

In some embodiments, the mediated cancer is selected from the group consisting of leukemia, prostate carcinoma, hepatocellular carcinoma, and lung cancer.

In some embodiments, the compounds disclosed herein can be used for ng cancer. In some embodiments, the cancer is a hematological cancer.

In some embodiments, the cancer is selected from the group consisting of brain and central nervous system (CNS) cancer, head and neck cancer, kidney cancer, ovarian cancer, pancreatic cancer, leukemia, lung cancer, lymphoma, myeloma, a, breast cancer, and prostate cancer. Preferably, a subject in need f is one who had, is having or is predisposed to developing brain and CNS cancer, kidney , ovarian cancer, pancreatic , leukemia, lymphoma, myeloma, and/or sarcoma. ary brain and l CNS cancer includes medulloblastoma, oligodendroglioma, atypical id/rhabdoid tumor, choroid plexus carcinoma, choroid plexus papilloma, ependymoma, glioblastoma, meningioma, neuroglial tumor, oligoastrocytoma, oligodendroglioma, and pineoblastoma. Exemplary ovarian cancer includes n clear cell adenocarcinoma, ovarian endomethrioid adenocarcinoma, and ovarian serous adenocarcinoma. Exemplary pancreatic cancer includes pancreatic ductal adenocarcinoma and pancreatic endocrine tumor. Exemplary sarcoma es chondrosarcoma, clear cell sarcoma of Attorney Docket No.: EPIZ-073/001WO (311622-2509) soft tissue, ewing sarcoma, gastrointestinal stromal tumor, osteosarcoma, rhabdomyosarcoma, and not otherwise specified (NOS) sarcoma. Alternatively, cancers to be treated by the compounds of the disclosure are non NHL cancers.

In some embodiments, the cancer is selected from the group consisting of acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL), medulloblastoma, oligodendroglioma, ovarian clear cell adenocarcinoma, ovarian endomethrioid adenocarcinoma, ovarian serous adenocarcinoma, pancreatic ductal adenocarcinoma, pancreatic endocrine tumor, malignant rhabdoid tumor, astrocytoma, atypical teratoid/rhabdoid tumor, d plexus carcinoma, choroid plexus papilloma, ependymoma, glioblastoma, meningioma, neuroglial tumor, oligoastrocytoma, oligodendroglioma, pineoblastoma, carcinosarcoma, ma, onadal germ cell tumor, enal rhabdoid tumor, schwannoma, skin us cell carcinoma, chondrosarcoma, clear cell sarcoma of soft tissue, ewing sarcoma, gastrointestinal stromal tumor, osteosarcoma, rhabdomyosarcoma, and not otherwise specified (NOS) sarcoma. Preferably, the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), medulloblastoma, ovarian clear cell adenocarcinoma, ovarian thrioid adenocarcinoma, pancreatic ductal adenocarcinoma, malignant rhabdoid tumor, atypical teratoid/rhabdoid tumor, choroid plexus carcinoma, choroid plexus papilloma, glioblastoma, meningioma, pineoblastoma, carcinosarcoma, enal rhabdoid tumor, noma, skin squamous cell carcinoma, chondrosarcoma, ewing sarcoma, epithelioid sarcoma, renal medullary carcinoma, diffuse large B-cell lymphoma, follicular lymphoma and/or NOS sarcoma.

In some ments, the cancer is lymphoma, leukemia or ma. In some embodiments, the cancer is lymphoma selected from the group ting of follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), and Burkitt’s lymphoma, and Non-Hodgkin’s ma. Preferably, the lymphoma is non-Hodgkin’s lymphoma (NHL), ular ma or diffuse large B-cell lymphoma. Alternatively, the leukemia is chronic myelogenous leukemia (CML), acute myeloid leukemia, acute lymphocytic leukemia or mixed lineage leukemia.

In some embodiments, the EHMT2-mediated disorder is a hematological disorder.

The compound(s) of the present disclosure inhibit the histone methyltransferase activity of EHMT2 or a mutant thereof and, accordingly, the present disclosure also provides methods for treating conditions and es the course of which can be influenced by modulating the ation status of es or other proteins, wherein said methylation status is mediated at least in part by the activity of EHMT2. In one aspect of the disclosure, certain compounds Attorney Docket No.: EPIZ-073/001WO (311622-2509) disclosed herein are candidates for treating, or preventing certain conditions, diseases, and disorders. Modulation of the methylation status of histones can in turn influence the level of sion of target genes activated by methylation, and/or target genes suppressed by methylation. The method includes administering to a subject in need of such treatment, a therapeutically ive amount of a compound of the present disclosure.

As used herein, a "subject" is hangeable with a "subject in need thereof", both of which refer to a subject having a disorder in which EHMT2-mediated protein methylation plays a part, or a subject having an increased risk of developing such disorder relative to the population at large. A ct" includes a mammal. The mammal can be e.g., a human or appropriate nonhuman mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig.

The subject can also be a bird or fowl. In one embodiment, the mammal is a human. A subject in need thereof can be one who has been previously diagnosed or fied as having cancer or a precancerous condition. A subject in need thereof can also be one who has (e.g., is suffering from) cancer or a precancerous condition. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a precancerous condition. A subject in need thereof can have refractory or resistant cancer (i.e., cancer that does not respond or has not yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the t in need thereof has cancer ence following remission on most recent y. In some embodiments, the subject in need thereof received and failed all known effective ies for cancer treatment. In some embodiments, the subject in need thereof received at least one prior therapy. In a red embodiment, the subject has cancer or a cancerous condition. In some embodiments, the cancer is leukemia, te carcinoma, hepatocellular carcinoma, and lung cancer.

As used herein, date compound" refers to a compound of the present sure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, that has been or will be tested in one or more in vitro or in vivo biological assays, in order to determine if that compound is likely to elicit a desired biological or medical response in a cell, , system, animal or human that is being sought by a researcher or clinician. A candidate compound is a compound of the present disclosure, or a ceutically acceptable salt, polymorph or solvate thereof. The ical or medical response can be the treatment of cancer. The biological or medical response can be Attorney Docket No.: EPIZ-073/001WO 2-2509) treatment or prevention of a cell erative er. The biological response or effect can also e a change in cell proliferation or growth that occurs in vitro or in an animal model, as well as other biological changes that are observable in vitro. In vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, er gene assays, in vitro cell viability assays, and the assays described herein.

In some embodiments, an in vitro biological assay that can be used includes the steps of (1) mixing a histone substrate (e.g., an isolated e sample or an isolated histone peptide representative of human histone H3 residues 1-15) with recombinant EHMT2 enzymes; (2) adding a compound of the disclosure to this mixture; (3) adding non-radioactive and 3H-labeled SAdenosyl nine (SAM) to start the reaction; (4) adding excessive amount of non-radioactive SAM to stop the reaction; (4) washing off the free non-incorporated 3H-SAM; and (5) detecting the quantity of 3H-labeled histone substrate by any methods known in the art (e.g., by a PerkinElmer TopCount platereader).

In some embodiments, an in vitro study that can be used includes the steps of (1) treating cancer cells (e.g., breast cancer cells) with a compound of this disclosure; (2) incubating the cells for a set period of time; (3) fixing the cells; (4) treating the cells with primary antibodies that bind to dimethylated histone substrates; (5) treating the cells with a secondary antibody (e.g. an antibody conjugated to an infrared dye); (6) detecting the quantity of bound dy by any methods known in the art (e.g., by a Licor Odyssey Infrared Scanner).

As used herein, "treating" or " describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a ceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or er, or to eliminate the disease, condition or disorder. The term "treat" can also include ent of a cell in vitro or an animal model.

A nd of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable ates for such purposes. As used herein, "preventing," "prevent," or "protecting against" describes reducing or eliminating the onset of the symptoms or cations of such disease, ion or disorder.

One skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Attorney Docket No.: EPIZ-073/001WO (311622-2509) Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., t Protocols in logy, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th edition (1990). These texts can, of , also be referred to in making or using an aspect of the disclosure.

As used herein, "combination therapy" or "co-therapy" includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, and at least a second agent as part of a specific treatment n intended to provide the beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.

The present disclosure also provides ceutical compositions comprising a nd of any of the Formulae bed herein in combination with at least one pharmaceutically acceptable excipient or carrier.

A "pharmaceutical composition" is a formulation containing the compounds of the present disclosure in a form suitable for stration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The ty of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration.

A variety of routes are contemplated, including oral, pulmonary, rectal, eral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, gual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, , nts, pastes, creams, lotions, gels, solutions, s and inhalants. In one embodiment, the active compound is mixed under sterile ions with a ceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

Attorney Docket No.: EPIZ-073/001WO 2-2509) As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, le for use in contact with the tissues of human beings and animals without ive toxicity, irritation, ic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

"Pharmaceutically acceptable excipient" means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and r ically nor otherwise undesirable, and includes excipient that is acceptable for nary use as well as human pharmaceutical use. A "pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more than one such excipient.

A pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., enous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous ation can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be ed in ampoules, disposable es or multiple dose vials made of glass or plastic.

A compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. In some embodiments, for treatment of cancers, a nd of the disclosure may be injected directly into tumors, ed into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to tute effective ent but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., cancer, precancer, and the like) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.

The term "therapeutically effective amount", as used herein, refers to an amount of a ceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to Attorney Docket No.: EPIZ-073/001WO (311622-2509) exhibit a detectable therapeutic or tory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and nt of the clinician. In a preferred aspect, the disease or condition to be treated is cancer. In another aspect, the disease or condition to be treated is a cell proliferative disorder.

For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal , usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be ined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical compositions that t large therapeutic indices are red. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the t, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular ation.

The pharmaceutical compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, ving, ating, -making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate sing of the active compounds into preparations that can be used ey Docket No.: EPIZ-073/001WO (311622-2509) pharmaceutically. Of course, the riate formulation is dependent upon the route of administration chosen. ceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, iostatic water, Cremophor EL (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various cterial and antifungal agents, for e, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic , for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable itions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by ed sterilization. Generally, dispersions are prepared by incorporating the active nd into a e e that ns a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of ation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Oral compositions generally include an inert diluent or an edible ceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active nd can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be Attorney Docket No.: EPIZ-073/001WO (311622-2509) prepared using a fluid carrier for use as a mouthwash, wherein the nd in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a r nature: a binder such as microcrystalline cellulose, gum tragacanth or n; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal n dioxide; a ning agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. ic administration can also be by transmucosal or transdermal means. For transmucosal or ermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and e, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.

Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the nd against rapid ation from the body, such as a controlled release ation, including implants and ncapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl e, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes ed to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically able carriers. These can be prepared according to s known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit ey Docket No.: EPIZ-073/001WO (311622-2509) ning a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

In therapeutic applications, the dosages of the ceutical compositions used in accordance with the disclosure vary ing on the agent, the age, weight, and clinical condition of the ent patient, and the experience and nt of the clinician or practitioner administering the therapy, among other factors ing the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the growth of the tumors and also ably causing complete regression of the cancer. Dosages can range from about 0.01 mg/kg per day to about 5000 mg/kg per day. In preferred aspects, dosages can range from about 1 mg/kg per day to about 1000 mg/kg per day. In an aspect, the dose will be in the range of about 0.1 mg/day to about 50 g/day; about 0.1 mg/day to about 25 g/day; about 0.1 mg/day to about 10 g/day; about 0.1 mg to about 3 g/day; or about 0.1 mg to about 1 g/day, in single, divided, or uous doses (which dose may be adjusted for the patient’s weight in kg, body e area in m2, and age in years). An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. In some embodiments, regression of a tumor in a patient may be measured with reference to the diameter of a tumor. Decrease in the diameter of a tumor indicates regression. Regression is also indicated by failure of tumors to reoccur after treatment has stopped. As used herein, the term "dosage effective manner" refers to amount of an active compound to produce the desired biological effect in a subject or cell.

The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

The compounds of the present disclosure are e of further forming salts. All of these forms are also plated within the scope of the claimed disclosure.

As used herein, aceutically acceptable salts" refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not d to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, Attorney Docket No.: EPIZ-073/001WO (311622-2509) from xic nic or organic acids. In some embodiments, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, , edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, esorcinic, hydrabamic, hydrobromic, hloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, , oxalic, pamoic, pantothenic, acetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly ing amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

Other examples of pharmaceutically acceptable salts e hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, ydroxybenzoyl)benzoic acid, cinnamic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-octenecarboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as lamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ration other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.

It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

The compounds of the present sure can also be prepared as esters, for example, pharmaceutically acceptable esters. In some embodiments, a carboxylic acid function group in a compound can be converted to its corresponding ester, e.g., a , ethyl or other ester. Also, an alcohol group in a compound can be converted to its ponding ester, e.g., acetate, propionate or other ester.

The compounds, or pharmaceutically acceptable salts f, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, leurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will recognize the advantages of certain routes of administration.

Attorney Docket No.: EPIZ-073/001WO (311622-2509) The dosage n utilizing the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical ion of the patient; the ty of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof ed. An ordinarily skilled physician or narian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the ion.

Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995). In an ment, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.

All tages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples rate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed sure. Based on the t disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.

In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer. nds designed, selected and/or optimized by methods bed above, once produced, can be characterized using a variety of assays known to those skilled in the art to ine whether the compounds have biological activity. In some embodiments, the molecules can be characterized by tional assays, including but not d to those assays described below, to determine whether they have a predicted activity, g activity and/or binding specificity.

Attorney Docket No.: EPIZ-073/001WO (311622-2509) Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the les described herein for activity, using techniques known in the art. General methodologies for ming high-throughput screening are described, for example, in Devlin (1998) High hput Screening, Marcel Dekker; and U.S. Patent No. 263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.

Various In vitro or in vivo biological assays are may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift , reporter gene assays, in vitro cell viability assays, and the assays described herein.

All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and dually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any ion as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for es of illustration and not limitation of the claims that follow.

Example 1: Synthesis of Compound 1 sis of 2-N-(4-methoxy[1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin yl]phenyl)N,6-dimethylpyrimidine-2,4-diamine Step 1: Synthesis of 3-iodomethoxyaniline: Attorney Docket No.: EPIZ-073/001WO (311622-2509) Into a 250-mL round-bottom flask was placed 2-iodomethoxynitrobenzene (6 g, 21.50 mmol, 1.00 equiv), Fe (3.61 g, 3.00 , NH4Cl (3.42 g, 63.94 mmol, 3.00 equiv), ethanol (50 mL), and water (10 mL). The resulting solution was stirred for 1 h at 85 oC. The solids were filtered out, and the resulting mixture was concentrated under vacuum. This resulted in 5.35 g (100%) of the title compound as a brown solid.

LC-MS: (ES, m/z): RT = 0.847 min, LCMS 53: m/z = 250 [M+1].

Step 2: sis of 2-N-(3-iodomethoxyphenyl)N,6-dimethylpyrimidine-2,4- Into a 250-mL round-bottom flask was placed 3-iodomethoxyaniline (5.25 g, 21.08 mmol, 1.00 equiv), 2-chloro-N,6-dimethylpyrimidinamine (3.31 g, 21.00 mmol, 1.00 equiv), trifluoroacetic acid (4.81 g, 42.55 mmol, 2.00 equiv), and iso-propanol (80 mL). The resulting solution was stirred for 3 h at 85 oC. The solids were collected by filtration. This resulted in 7.2 g (92%) of the title compound as a solid.

LC-MS: (ES, m/z): RT =1.041 min, LCMS 15: m/z = 371 [M+1]. 1H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.95 (s, 1H), 8.14 (d, J = 2.6 Hz, 1H), 7.50 (d, J = 2.6 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H), 6.02 (s, 1H), 3.81 (s, 3H), 2.90 (d, J = 4.6 Hz,3H), 2.24 (s, 3H).

Step 3: Synthesis of tert-butyl 1-(2-methoxy[[4-methyl(methylamino)pyrimidin no]phenyl)-1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridinecarboxylate: Into a 25-mL round-bottom flask was placed 2-N-(3-iodomethoxyphenyl)N,6- dimethylpyrimidine-2,4-diamine (2.8 g, 7.56 mmol, 1.00 equiv), CuI (580 mg, 3.04 mmol, 0.40 equiv), K3PO4 (4.88 g, 22.98 mmol, 3.00 equiv), (1R,2R)N,2-N-dimethylcyclohexane-1,2- diamine (300 mg, 2.10 mmol, 0.20 equiv), tert-butyl 2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine carboxylate (2 g, 8.96 mmol, 1.10 equiv), and DMSO (10 mL). The ing solution was stirred for 36 h at 140 oC in an oil bath. The crude product was purified by C18 column: ACN:H2O (0.05%TFA)=1/5. This resulted in 1.4 g (40%) of the title compound as a yellow solid.

LC-MS: (ES, m/z): RT =1.552 min, LCMS33 : m/z = 466 [M+1].

Step 4: Synthesis of 2-N-(4-methoxy[1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin yl]phenyl)N,6-dimethylpyrimidine-2,4-diamine: Into a 25-mL round-bottom flask was placed tert-butyl 1-(2-methoxy[[4-methyl (methylamino)pyrimidinyl]amino]phenyl)-1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine carboxylate (0.5 g, 1.07 mmol, 1.00 equiv), trifluoroacetic acid (1 mL), and dichloromethane (5 mL). The resulting solution was stirred for 1 h at 25 oC. The ing mixture was concentrated Attorney Docket No.: EPIZ-073/001WO (311622-2509) under . The crude product was ed by PLC; mobile phase, water (10 mmol/L NH4HCO3) and ACN (23.0% ACN up to 34.0% in 10 min); detector, UV 254/220nm. This resulted in 55.9 mg (7%) of the title compound as a light yellow solid.

Example 2: Synthesis of Compound 2 Synthesis of 2-N-(4-methoxy[1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin yl]phenyl)N,6-dimethylpyrimidine-2,4-diamine Synthesis of 2-N-(4-methoxy[1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridinyl]phenyl) N,6-dimethylpyrimidine-2,4-diamine: Into a 100-mL round-bottom flask was placed -methoxy[1H,4H,5H,6H,7H- pyrazolo[4,3-c]pyridinyl]phenyl)N,6-dimethylpyrimidine-2,4-diamine (500 mg, 1.37 mmol, 1.00 equiv), methanol (6 mL), and formaldehyde (82 mg, 2.56 mmol, 1.00 equiv) and stirred for min at 25 oC. Then NaBH3CN (345 mg, 5.49 mmol, 4.00 equiv), HOAc (0.02 mL) was added.

The resulting solution was stirred for 2 h at 25 oC. The pH value of the solution was adjusted to 8 with sodium bicarbonate. The resulting solution was extracted with 2x50 mL of dichloromethane and the organic layers combined and concentrated under vacuum. The crude product was purified by prep-HPLC; mobile phase, Water(10 mmol/L NH4HCO3) and ACN (23.0% ACN up to 34.0% in 10 min); detector, UV 254/220 nm. This resulted in 16.3 mg (2%) of the title compound as a white solid. e 3: sis of Compound 4 Synthesis of 2-N-[3-[3-(cyclopentylmethyl)-1H-pyrazolyl]methoxyphenyl] N,6-dimethylpyrimidine-2,4-diamine; trifluoroacetic acid ey Docket No.: 73/001WO (311622-2509) Step 1: sis of 5-(pyrrolidinylmethyl)-1H-pyrazole: Into a 250-mL round-bottom flask was placed 1H-pyrazolecarbaldehyde (500 mg, 5.20 mmol, 1.00 equiv), methanol (20 mL), NaBH3CN (656 mg, 10.44 mmol, 2.01 equiv), and pyrrolidine (370 mg, 5.20 mmol, 1.00 equiv). The resulting solution was stirred for 1 h at 25 oC.

The residue was applied onto a silica gel column with H2O:CH3CN (89/11). This resulted in 350 mg (44%) the title compound as a yellow oil.

LC-MS: (ES, m/z): RT=0.15 min，LCMS32，m/z=152.1 [M+1].

Step 2: Synthesis of 2-N-[3-[3-(cyclopentylmethyl)-1H-pyrazolyl]methoxyphenyl]- 4-N,6-dimethylpyrimidine-2,4-diamine, trifluoroacetic acid: Into a 30-mL round-bottom flask was placed 5-(pyrrolidinylmethyl)-1H-pyrazole (190 mg, 1.26 mmol, 1.00 equiv), DMSO (4 mL), -iodomethoxyphenyl)N,6- dimethylpyrimidine-2,4-diamine (230 mg, 0.62 mmol, 0.49 equiv), 1-N,2-N- dimethylcyclohexane-1,2-diamine (73 mg, 0.51 mmol, 0.41 equiv), CuI (47 mg, 0.25 mmol, 0.20 equiv), and K3PO4 (400 mg, 1.88 mmol, 1.50 equiv). The resulting solution was stirred for 12 h at 120 oC. The crude product was purified by prep-HPLC; Mobile Phase A:Water/0.05%TFA, Mobile Phase B: ACN. This resulted in 18.2 mg (3%) of the title compound as a white solid.

LC-MS: (ES, m/z): RT=1.06 min, LCMS28, m/z=394.2 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.26 (d, J = 2.5 Hz, 1H), 8.12 (d, J = 2.7 Hz, 1H), 7.74 – 7.65 (m, 1H), 7.26 (d, J = 9.0 Hz, 1H), 6.66 (d, J = 2.5 Hz, 1H), 5.99 (d, J = 1.1 Hz, 1H), 4.48 (s, 2H), 3.93 (d, J = 5.7 Hz, 3H), 3.65 (s, 2H), 3.30 (d, J = 7.4 Hz, 2H), 3.02 (s, 3H), 2.34 – 2.29 (m, 3H), 2.21 – 2.11 (m, 2H), 2.10 – 1.99 (m, 2H).

Step 3: Synthesis of 5-(pyrrolidinylmethyl)-1H-pyrazole: Into a 250-mL round-bottom flask was placed 1H-pyrazolecarbaldehyde (500 mg, 5.20 mmol, 1.00 equiv), methanol (20 mL), NaBH3CN (656 mg, 10.44 mmol, 2.01 , and pyrrolidine (370 mg, 5.20 mmol, 1.00 equiv). The resulting on was stirred for 1 h at 25 oC.

Attorney Docket No.: EPIZ-073/001WO (311622-2509) The e was applied onto a silica gel column with H2O:CH3CN (89/11). This resulted in 350 mg (44%) of 5-(pyrrolidinylmethyl)-1H-pyrazole as a yellow oil.

LC-MS: (ES, m/z): RT=0.15min, LCMS32, m/z=152.1[M+1].

Step 4: Synthesis of 2-N-[3-[3-(cyclopentylmethyl)-1H-pyrazolyl]methoxyphenyl]- 4-N,6-dimethylpyrimidine-2,4-diamine, trifluoroacetic acid: Into a 30-mL bottom flask was placed 5-(pyrrolidinylmethyl)-1H-pyrazole (190 mg, 1.26 mmol, 1.00 , DMSO (4 mL), 2-N-(3-iodomethoxyphenyl)N,6- dimethylpyrimidine-2,4-diamine (230 mg, 0.62 mmol, 0.49 equiv), 1-N,2-N- dimethylcyclohexane-1,2-diamine (73 mg, 0.51 mmol, 0.41 equiv), CuI (47 mg, 0.25 mmol, 0.20 equiv), and K3PO4 (400 mg, 1.88 mmol, 1.50 equiv). The resulting solution was stirred for 12 h at 120 oC. The crude product was purified by prep-HPLC; Mobile Phase r/0.05%TFA, Mobile Phase B: ACN. This resulted in 18.2 mg (3%) of the title compound as a white solid.

Example 4: Synthesis of Compound 5 Synthesis of 2-N-[4-methoxy[4-(pyrrolidinylmethyl)-1H-pyrazolyl]phenyl]- 4-N,6-dimethylpyrimidine-2,4-diamine: Step 1: Synthesis of 4-(pyrrolidinylmethyl)-1H-pyrazole: Into a 250-mL round-bottom flask was placed 1H-pyrazolecarbaldehyde (1 g, 10.41 mmol, 1.00 equiv), Ti(OiPr)4 (10 g), ethanol (20 mL), pyrrolidine (740 mg, 10.40 mmol, 1.00 equiv), and NaBH3 (792 mg). The resulting solution was stirred for 2 h at 25 oC. The residue was d onto a silica gel column with H2O:CH3CN (83/17). This resulted in 570 mg (36%) of the title compound as a white solid.

LC-MS: (ES, m/z): RT = 0.395 min, LCMS31, m/z =152.2 [M+1].

Step 2: Synthesis of 2-N-[4-methoxy[4-(pyrrolidinylmethyl)-1H-pyrazol yl]phenyl]N,6-dimethylpyrimidine-2,4-diamine, trifluoroacetic acid: Into a 30-mL round-bottom flask was placed rolidinylmethyl)-1H-pyrazole (80 mg, 0.53 mmol, 1.00 equiv), DMSO (5 mL), K3PO4 (171 mg, 0.81 mmol, 1.52 equiv), CuI (21 Attorney Docket No.: EPIZ-073/001WO (311622-2509) mg, 0.11 mmol, 0.21 equiv), and 2-N-(3-iodomethoxyphenyl)N,6-dimethylpyrimidine-2,4- diamine (100 mg, 0.27 mmol, 0.51 equiv). The resulting on was stirred for 16 h at 140 oC.

The crude product was ed by prep-HPLC; Mobile Phase A:Water/0.05%TFA, Mobile Phase B: ACN. This resulted in 26.6 mg (10%) of the title compound as a light yellow solid.

Example 5: Synthesis of Compound 8 Synthesis of 2-N-(4-methoxy[4H,5H,6H,7H-[1,2,4]triazolo[1,5-a]pyrazin yl]phenyl)N,6-dimethylpyrimidine-2,4-diamine hydrochloride: Synthesis of 2-bromo-[1,2,4]triazolo[1,5-a]pyrazine: Into a 250-mL round-bottom flask was placed [1,2,4]triazolo[1,5-a]pyrazinamine (5 g, 37.00 mmol, 1.00 equiv), NaNO2 (2 g, 28.99 mmol, 0.78 equiv), CuBr (1.8 g), AcOH (40 mL), and water (15 mL), HBr (25 mL). The resulting solution was stirred for 10 h at room temperature.

The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). This resulted in 1.5 g (20%) of the title compound as a white solid.

LC-MS: (ES, m/z): RT = 1.189 min, LCMS 07: m/z = 199 [M+1].

Step 1: Synthesis of (2-methoxy[[4-methyl(methylamino)pyrimidin yl]amino]phenyl)boronic acid: Into a 500-mL bottom flask purged and maintained with an inert here of nitrogen was placed 2-N-(3-iodomethoxyphenyl)N,6-dimethylpyrimidine-2,4-diamine (2 g, Attorney Docket No.: 73/001WO (311622-2509) .40 mmol, 1.00 equiv), B2pin2 (5 g), KOAc (3 g, 30.57 mmol, 5.66 equiv), Pd(dppf)Cl2 (600 mg, 0.82 mmol, 0.15 equiv), and dioxane (200 mL). The resulting solution was d for 2 h at 80 oC in an oil bath. The resulting mixture was concentrated under . The e was applied onto a silica gel column with dichloromethane/methanol (20:1). This resulted in 1.2 g (77%) of the title compound as a yellow solid.

LC-MS: (ES, m/z): RT = 0.981 min, LCMS 07: m/z = 289 [M+1].

Step 2: Synthesis of 2-N-(4-methoxy[[1,2,4]triazolo[1,5-a]pyrazinyl]phenyl) N,6-dimethylpyrimidine-2,4-diamine: Into a 125-mL round-bottom flask purged and maintained with an inert atmosphere of en was placed (2-methoxy[[4-methyl(methylamino)pyrimidin yl]amino]phenyl)boronic acid (500 mg, 1.74 mmol, 1.00 equiv), 2-bromo-[1,2,4]triazolo[1,5- zine (350 mg, 1.76 mmol, 1.01 equiv), Pd(PPh3)4 (100 mg, 0.09 mmol, 0.05 equiv), K2CO3 (800 mg, 2.46 mmol, 1.41 equiv), dioxane (8 mL), and water(1.5 mL). The resulting solution was stirred for 2 h at 80 oC in an oil bath. The resulting e was trated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol . This resulted in 600 mg (95%) of the title compound as a white solid.

LC-MS: (ES, m/z): RT = 1.003 min, LCMS 07: m/z = 363 [M+1].

Step 3: Synthesis of 2-N-(4-methoxy[4H,5H,6H,7H-[1,2,4]triazolo[1,5-a]pyrazine yl]phenyl)N,6-dimethylpyrimidine-2,4-diamine: Into a 125-mL round-bottom flask was placed 2-N-(4-methoxy[[1,2,4]triazolo[1,5- a]pyrazinyl]phenyl)N,6-dimethylpyrimidine-2,4-diamine (300 mg, 0.83 mmol, 1.00 equiv), PtO2 (20 mg), methanol (10 mL), and hydrogen. The resulting solution was stirred for 2 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum.

This resulted in 280 mg (92%) of the title compound as a yellow solid.

LC-MS: (ES, m/z): RT = 2.985 min, LCMS 07: m/z = 367 [M+1].

Step 4: Synthesis of 2-N-(4-methoxy[4H,5H,6H,7H-[1,2,4]triazolo[1,5-a]pyrazin yl]phenyl)N,6-dimethylpyrimidine-2,4-diamine hydrochloride: Into a 25-mL round-bottom flask was placed 2-N-(4-methoxy[4H,5H,6H,7H- [1,2,4]triazolo[1,5-a]pyrazinyl]phenyl)N,6-dimethylpyrimidine-2,4-diamine (100 mg, 0.27 mmol, 1.00 equiv), and hydrogen chloride (2 mL). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product ( mL) was purified by Flash-Prep-HPLC; mobile phase, water (0.05%HCl) and ACN (5% ACN up Attorney Docket No.: EPIZ-073/001WO (311622-2509) to 15% in 7 min), detector, 254/220 nm. This resulted in 40.1 mg (97%) of the title compound as a white solid.

Example 6: Synthesis of Compound 10 Synthesis of 2-N-(4-methoxy[5-methyl-octahydro-1H-pyrazolidino[4,3-c]pyridin- 2-yl]cyclohexyl)N,6-dimethyl-1,3-diazinane-2,4-diamine; trifluoroacetic acid: sis of 2-N-(4-methoxy[5-methyl-octahydro-1H-pyrazolidino[4,3-c]pyridin lohexyl)N,6-dimethyl-1,3-diazinane-2,4-diamine: Into a 25-mL round-bottom flask was placed -methoxy[2H,4H,5H,6H,7H- pyrazolo[4,3-c]pyridinyl]phenyl)N,6-dimethylpyrimidine-2,4-diamine (100 mg, 0.27 mmol, 1.00 equiv), HCHO (16 mg, 2.00 equiv), methanol (2 mL), NaBH3CN (69 mg, 1.10 mmol, 4.00 equiv), and acetic acid (0.002 mL). The resulting solution was stirred for 30 min at 25 oC. The resulting solution was allowed to react, with stirring, for an additional 2 h at 25 oC. The resulting mixture was concentrated under . The crude product was purified by Flash-prep-HPLC; mobile phase, H2O/ACN=38%, detector, UV 254 nm. This resulted in 10 mg (7%) of the title compound as a white solid. e 7: Synthesis of Compound 12 Synthesis of :2-N-[4-methoxy(1H-pyrazolyl)phenyl]N,6-dimethylpyrimidine- 2,4-diamine: Synthesis of 2-N-[4-methoxy(1H-pyrazolyl)phenyl]N,6-dimethylpyrimidine-2,4- diamine: Attorney Docket No.: EPIZ-073/001WO (311622-2509) Into a 100-mL round-bottom flask was placed 2-N-(3-iodomethoxyphenyl)N,6- ylpyrimidine-2,4-diamine (500 mg, 1.35 mmol, 1.00 equiv), 1,4-dioxane (15 mL), water (5 mL), Cs2CO3 (1321.6 mg, 4.06 mmol, 3.00 equiv), Pd(pph3)4 (156.2 mg, 0.14 mmol, 0.10 equiv), and 4-(tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (393 mg, 2.03 mmol, 1.50 equiv). The resulting solution was stirred for 6 h at 80 oC. The resulting solution was diluted with 50 mL of water, and the resulting solution was extracted with 3x50 mL of ethyl acetate. The organic layers was washed with 3x50 mL of brine and trated under vacuum. The crude product was purified by prep-HPLC; mobile phase, water (10 mmol/L NH4HCO3) and ACN (10.0% ACN up to 60.0% in 5 min); detector, UV 254/220 nm. This resulted in 36.9 mg (8.8%) of the title compound as a white solid.

Example 8: sis of Compound 14 Synthesis of 2-N-[3-(4-cyclopropyl-1H-pyrazolyl)methoxyphenyl]N,6- dimethylpyrimidine-2,4-diamine: Synthesis of 2-N-[3-(4-cyclopropyl-1H-pyrazolyl)methoxyphenyl]N,6- dimethylpyrimidine-2,4-diamine: Into a 50-mL bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 2-N-(3-iodomethoxyphenyl)N,6-dimethylpyrimidine-2,4-diamine (300 mg, 0.81 mmol, 1.00 equiv), 4-cyclopropyl-1H-pyrazole hydrochloride (140 mg, 0.97 mmol, 1.20 equiv), (1R)N,2-N-dimethylcyclohexane-1,2-diamine (80 mg, 0.56 mmol, 0.6 equiv), potassium carbonate (335 mg, 2.42 mmol, 3.00 equiv), DMSO (8 mL), and CuI (123 mg, 0.65 mmol, 0.80 equiv). The resulting solution was d for 4 h at 140 oC in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by PLC; mobile phase, water (10 mmol/L NH4HCO3) and ACN (20.0% ACN up to 45.0% in 7 min), detector, UV 254nm. This resulted in 38.9 mg (14%) of the title compound as a white solid. e 9: Synthesis of Compound 15 Attorney Docket No.: EPIZ-073/001WO (311622-2509) Synthesis of 2-N-[4-methoxy(1H-pyrazolyl)phenyl]N,6-dimethylpyrimidine- 2,4-diamine; trifluoroacetic acid: Synthesis of 2-N-[4-methoxy(1H-pyrazolyl)phenyl]N,6-dimethylpyrimidine-2,4- diamine: Into a 100-mL round-bottom flask was placed DMSO (20 mL), 2-N-(3-iodo methoxyphenyl)N,6-dimethylpyrimidine-2,4-diamine (300 mg, 0.81 mmol, 1.00 equiv), 1H- pyrazole (165 mg, 2.42 mmol, 2.99 equiv), (1R,2R)N,2-N-dimethylcyclohexane-1,2-diamine (92 mg, 0.65 mmol, 0.80 equiv), CuI (62 mg, 0.33 mmol, 0.40 equiv), and K3PO4 (516 mg, 2.43 mmol, 3.00 equiv). The flask was purged and maintained with N2. The resulting solution was stirred for 12 h at 120 oC, then trated under vacuum. The crude product (102 mg) was purified by prep-HPLC; mobile phase, Water (0.05%TFA) and ACN (3.0% ACN up to 18.0% in 8 min), or, UV 254/220nm. This ed in 53.3 mg (15%) of the title compound as a gray solid.

Example 10: Synthesis of Compound 22 Synthesis of 2-N-(4-methoxy[2H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridin yl]phenyl)N,6-dimethylpyrimidine-2,4-diamine hydrochloride: Step 1: Synthesis of tert-butyl 2-(2-methoxy[[4-methyl(methylamino)pyrimidin yl]amino]phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridinecarboxylate: Into a 25-mL round-bottom flask purged and ined with an inert atmosphere of nitrogen was placed -iodomethoxyphenyl)N,6-dimethylpyrimidine-2,4-diamine (1 g, 2.70 mmol, 1.00 equiv), CuI (15 mg, 0.08 mmol, 0.10 equiv), DMSO (10 mL), K3PO4 (2.51 g, 8.12 mmol, 3.00 equiv), (1R,2R)N,2-N-dimethylcyclohexane-1,2-diamine (110 mg, 0.54 mmol, 0.20 equiv), and tert-butyl 2H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridinecarboxylate (1.2 g, 5.37 Attorney Docket No.: EPIZ-073/001WO 2-2509) mmol, 2.00 equiv). The resulting solution was stirred for 4 days at 140 oC in an oil bath. The solids were filtered out. The residue was applied onto a silica gel column with H2O (0.05%TFA):ACN (2:1). This resulted in 200 mg (15%) of the title nd as a white solid.

LC-MS: (ES, m/z): RT = 1.142 min; LCMS 33: m/z =466 [M+1]. 1H-NMR: δ8.55 (d, J = 2.7 Hz, 1H), 8.27 (d, J = 2.7 Hz, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.41 (d, J = 9.0 Hz, 1H), 6.06 (d, J = 1.2 Hz, 1H), 4.42 (s, 2H), 3.91 (s, 3H), 3.56 (t, J = 6.3 Hz, 2H), 3.13 – 2.97 (m, 5H), 2.48 – 2.26 (m, 3H), 1.52 (s, 9H).

Step 2: sis of 2-N-(4-methoxy[2H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridin yl]phenyl)N,6-dimethylpyrimidine-2,4-diamine hydrochloride: Into a 50-mL round-bottom flask was placed tert-butyl 2-(2-methoxy[[4-methyl (methylamino)pyrimidinyl]amino]phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine carboxylate (200 mg, 0.43 mmol, 1.00 equiv), trifluoroacetic acid (147 mg, 1.30 mmol, 3.00 equiv), and dichloromethane (10 mL). The resulting solution was stirred for 14 h at 25 oC. The resulting mixture was concentrated under vacuum. The residue was d onto a silica gel column with H2O (0.05%TFA):ACN (1:1). This resulted in 9.3 mg (5%) of the title compound as a light yellow solid.

Example 11: Synthesis of Compound 23 Synthesis of 2-N-[3-[4-(aminomethyl)-1H-pyrazolyl]methoxyphenyl]N,6- dimethylpyrimidine-2,4-diamine; trifluoroacetic acid: Step 1: Synthesis of utyl N-[[1-(2-methoxy[[4-methyl (methylamino)pyrimidinyl]amino]phenyl)-1H-pyrazolyl]methyl]carbamate: Into a 30-mL round-bottom flask was placed 2-N-(3-iodomethoxyphenyl)N,6- dimethylpyrimidine-2,4-diamine (100 mg, 0.27 mmol, 1.00 equiv), DMSO (4 mL), CuI (21 mg, 0.11 mmol, 0.41 equiv), K3PO4 (172 mg, 0.81 mmol, 3.00 equiv), utyl N-(1H-pyrazol ylmethyl)carbamate (212 mg, 1.07 mmol, 3.98 equiv), and 1-N,2-N-dimethylcyclohexane-1,2- diamine (31 mg, 0.22 mmol, 0.81 equiv). The resulting solution was stirred for 12 h at 120 oC. The Attorney Docket No.: EPIZ-073/001WO 2-2509) crude product was purified by flash-prep-HPLC; mobile phase, H2O/CH3CN=1/1; Detector, UV 254 nm. This resulted in 80 mg (67%) of the title nd as white solid.

LC-MS: (ES, m/z): RT=1.096 min，LCMS28，m/z=440.2 [M+1].

Step 2: Synthesis of 2-N-[3-[4-(aminomethyl)-1H-pyrazolyl]methoxyphenyl] N,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom flask was placed tert-butyl N-[[1-(2-methoxy[[4-methyl (methylamino)pyrimidinyl]amino]phenyl)-1H-pyrazolyl]methyl]carbamate (80 mg, 0.18 mmol, 1.00 equiv), dichloromethane (3 mL), and trifluoroacetic acid (1 mL). The resulting solution was stirred for 1 h at 25 oC. The crude product was purified by prep-HPLC; Mobile Phase r/0.05%TFA, Mobile Phase B: ACN. This resulted in 52.4 mg of the title compound as a white solid.

Example 12: Synthesis of Compound 26 Synthesis of 2-N-[4-methoxy(4,5,6,7-tetrahydro-1H-indazolyl)phenyl]N,6- dimethylpyrimidine-2,4-diamine oroacetic acid: Step 1: Synthesis of tert-butyl ethoxy((4-methyl(methylamino)pyrimidin yl)amino)phenyl)hydrazinecarboxylate: Into a 100-mL bottom flask was placed 2-N-(3-iodomethoxyphenyl)N,6- dimethylpyrimidine-2,4-diamine (2 g, 5.40 mmol, 1.00 equiv), DMSO (20 mL), 3rd-brettphos (388 mg), (tert-butoxy)carbohydrazide (566 mg, 4.28 mmol, 0.79 equiv), cesium carbonate (4.2 g, 12.85 mmol, 2.38 equiv). The resulting solution was stirred for 12 h at 80 oC. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 5x100 mL of water and 1x100 mL of sodium chloride. The Attorney Docket No.: 73/001WO (311622-2509) mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.5 g (74%) of the title compound as a brown solid.

LC-MS: (ES, m/z): RT=0.699 min, LCMS30, m/z=375.1[M+1].

Step 2: Synthesis of (2E)[(dimethylamino)methylidene]cyclohexanone: Into a 30-mL round-bottom flask was placed exanone (1 g, 10.19 mmol, 1.00 equiv). DMFDMA (1.3 g, 56.46 mmol, 5.54 equiv). The resulting solution was stirred for 12 h at 80 oC. The crude product was purified by Flash-Prep-HPLC; mobile phase, dichloromethane/ CH3OH = 60/40; Detector, UV 254 nm. This resulted in 150 mg (10%) of the title nd as a yellow oil.

LC-MS: (ES, m/z): RT=4.90 min, GCMS04, m/z=153 [M].

Step 3: Synthesis of 2-N-(3-hydrazinylmethoxyphenyl)N,6-dimethylpyrimidine- 2,4-diamine: Into a 100-mL bottom flask was placed Nmethoxy[[4-methyl (methylamino)pyrimidinyl]amino]phenyl)(tert-butoxy)carbohydrazide (600 mg, 1.60 mmol, 1.00 , dichloromethane (5 mL), and trifluoroacetic acid (3 mL). The resulting solution was stirred for 1 h at 25 oC. The resulting mixture was concentrated under vacuum. This resulted in 300 mg (68%) of the title nd as a black solid.

LC-MS: (ES, m/z): RT=0.500 min, LCMS45, m/z=275.2[M+1].

Step 4: Synthesis of 2-N-[4-methoxy(4,5,6,7-tetrahydro-1H-indazolyl)phenyl] N,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom flask was placed 2-N-(3-hydrazinylmethoxyphenyl)N,6- dimethylpyrimidine-2,4-diamine (180 mg, 0.66 mmol, 1.00 equiv), (2E) [(dimethylamino)methylidene]cyclohexanone (100 mg, 0.65 mmol, 0.99 equiv), and hydrogen chloride (0.1 mL). The resulting solution was stirred for 1 h at 70 oC. The crude product was purified by prep-HPLC; Mobile Phase A:Water/0.05%TFA, Mobile Phase B: ACN. This ed in 22.5 mg (7%) of the title compound as a light yellow solid.

Example 13: Synthesis of Compound 27 Synthesis of 5-fluoroN-(4-methoxy[2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin yl]phenyl)N,6-dimethylpyrimidine-2,4-diamine trifluoroacetic acid: Attorney Docket No.: EPIZ-073/001WO (311622-2509) Synthesis of 2,4-dichlorofluoromethylpyrimidine: Into a 250-mL 3-necked round-bottom flask was placed bromo(methyl) magnesium (6 mL, 1.50 equiv), oxolane (10 mL), 2,4-dichlorofluoropyrimidine (2 g, 11.98 mmol, 1.00 equiv), ethylene glycol dimethyl ether (10 mL), TEA (2 mL), and diiodane (3 g, 11.82 mmol, 1.00 equiv).

The resulting solution was d for 1 h at 15 oC. The resulting solution was allowed to react, with stirring, for an additional 1 min while the ature was maintained at -5 oC in an ice/salt bath. The reaction was then quenched by the addition of 100 mL of water. The resulting on was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 700 mg (32%) of the title compound as a yellow oil.

LC-MS: (ES, m/z): RT = 0.84 min, LCMS15: m/z = 181 [M+1].

Synthesis of 2-chlorofluoro-N,6-dimethylpyrimidinamine: Into a 50-mL round-bottom flask was placed 2,4-dichlorofluoromethylpyrimidine (700 mg, 3.87 mmol, 1.00 equiv), CH3NH2.THF (5 mL), TEA (1.2 g, 11.86 mmol, 3.00 equiv), tetrahydrofuran (10 mL). The ing solution was stirred for 2 h at 20 oC. The ing mixture was concentrated under vacuum. The crude product (700 mg) was purified by prep-HPLC; mobile phase, CH3CN/H2O=30%/70% increasing to H2O=40%/60% within 10 min; detector, UV 254 nm. This resulted in 400 mg (59%) of the title compound as an off-white solid.

LC-MS: (ES, m/z): RT = 1.01 min, LCMS15: m/z = 176.03 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 2.97 (s, 3H), 2.27 (d, J = 3.0 Hz, 3H).

Synthesis of tert-butyl (3E)[(dimethylamino)methylidene]oxopiperidine carboxylate (for use in Step 2): Attorney Docket No.: EPIZ-073/001WO (311622-2509) Into a 20-mL round-bottom flask was placed tert-butyl iperidinecarboxylate (1 g, 5.02 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL), DMF-DMA (598 mg, 1.10 equiv).

The resulting solution was stirred for 6 h at 80 oC in an oil bath. The crude product (1 g) was purified by flash-prep-HPLC; mobile phase, CH3CN/ H2O (NH4HCO3) =30%/70% increasing to CH3CN/H2O(NH4HCO3)=40%/60% within 10 min, detector, UV 254 nm. This resulted in 800 mg (63%) of the title compound as a yellow oil.

LC-MS: (ES, m/z): RT = 0.95min, LCMS34: m/z = 255 [M+1].

Step 1: Synthesis of (2-methoxynitrophenyl)hydrazine: Into a 250-mL 3-necked round-bottom flask was placed 2-methoxynitroaniline (2 g, 11.89 mmol, 1.00 equiv), and hydrogen chloride (16 mL). To this solution was added NaNO2 (904 mg, 13.10 mmol, 1.10 equiv) at -10 oC, and the resulting mixture was stirred for 1 h. To this solution was added SnCl2·2 H2O (5.45 g, 24.15 mmol, 2.20 equiv) dissolved in HCl. The resulting solution was stirred for 30 min at -25 oC. The solids were ted by filtration. The solids of the solution were dissolved in potassium hydroxide (25%). This resulted in 1.3 g (60%) of the title compound as a red solid.

LC-MS: (ES, m/z): RT = 0.34 min, LCMS45: m/z = 184.07 [M+1]. 1H NMR (400 MHz, 6) δ 7.79 (d, J = 2.9 Hz, 1H), 7.55 (dd, J = 8.8, 2.9 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.65 (s, 1H), 4.17 (s, 2H), 3.90 (s, 3H).

Step 2: Synthesis of tert-butyl 1-(2-methoxynitrophenyl)-1H,4H,5H,6H,7H- pyrazolo[4,3-c]pyridinecarboxylate: Into a 50-mL round-bottom flask was placed (2-methoxynitrophenyl)hydrazine (200 mg, 1.09 mmol, 1.00 equiv), HOAc (197 mg, 3.28 mmol, 3.00 , tert-butyl (3E) [(dimethylamino)methylidene]oxopiperidinecarboxylate (278 mg, 1.09 mmol, 1.00 equiv), and methanol (10 mL). The resulting on was stirred for 3 h at 65 oC in an oil bath. The ing mixture was concentrated under vacuum. The resulting on was diluted with 10 mL of H2O. The resulting solution was extracted with 3x20 mL of chloromethane and the organic layers combined. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (20%B). This resulted in 240 mg (59%) of the title compound as a yellow solid.

LC-MS: (ES, m/z): RT = 1.43 min, LCMS31: m/z = 375.16 [M+1].

Step 3: Synthesis of tert-butyl 1-(5-aminomethoxyphenyl)-1H,4H,5H,6H,7H- pyrazolo[4,3-c]pyridinecarboxylate: Attorney Docket No.: EPIZ-073/001WO (311622-2509) Into a 50-mL round-bottom flask was placed tert-butyl 1-(2-methoxynitrophenyl)- 1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridinecarboxylate (200 mg, 0.53 mmol, 1.00 , methanol (20 mL), Raney-Ni, hydrogen. The resulting solution was stirred for 1 h at 20 oC. The solids were filtered out. The resulting mixture was trated under vacuum. This resulted in 130 mg (71%) of as yellow oil.

LC-MS: (ES, m/z): RT = 1.00min, LCMS33: m/z = 345.16 [M+1].

Step 4: Synthesis of 5-fluoroN-(4-methoxy[2H,4H,5H,6H,7H-pyrazolo[4,3- c]pyridinyl]phenyl)N,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom flask was placed tert-butyl 2-(5-aminomethoxyphenyl)- 2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridinecarboxylate (110 mg, 0.32 mmol, 1.00 equiv), trifluoroacetic acid (180.7 mg, 1.60 mmol, 5.00 equiv), IPA (5 mL), and rofluoro-N,6- dimethylpyrimidinamine (56 mg, 0.32 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at 80 oC in an oil bath. The resulting mixture was concentrated under vacuum. The crude t (110 mg) was ed by flash-prep-HPLC; mobile phase, H2O(TFA):CH3CN increasing to H2O(TFA):CH3CN=20% within 20 min, detector, UV 254 nm. This resulted in 18.3 mg (12%) of the title compound as a light yellow solid.

Example 14: Synthesis of Compound 28 Synthesis of 5-fluoroN-(4-methoxy[1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin yl]phenyl)N,6-dimethylpyrimidine-2,4-diamine trifluoroacetic acid: Step 1: Synthesis of tert-butyl 1-(5-aminomethoxyphenyl)-1H,4H,5H,6H,7H- pyrazolo[4,3-c]pyridinecarboxylate: Into a 50-mL round-bottom flask was placed utyl 1-(2-methoxynitrophenyl)- 5H,6H,7H-pyrazolo[4,3-c]pyridinecarboxylate (200 mg, 0.53 mmol, 1.00 equiv), methanol (20 mL), Raney-Ni, and hydrogen. The resulting solution was stirred for 1 h at 20 oC.

The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted Attorney Docket No.: EPIZ-073/001WO (311622-2509) in 130 mg (71%) of utyl 1-(5-aminomethoxyphenyl)-1H,4H,5H,6H,7H-pyrazolo[4,3- dinecarboxylate as a yellow oil.

LC-MS: (ES, m/z): RT = 0.99 min, LCMS15: m/z = 345.19 [M+1].

Step 2: Synthesis of 5-fluoroN-(4-methoxy[1H,4H,5H,6H,7H-pyrazolo[4,3- dinyl]phenyl)N,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom flask was placed tert-butyl 1-(5-aminomethoxyphenyl)- 1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridinecarboxylate (100 mg, 0.29 mmol, 1.00 equiv), IPA (10 mL), 2-chlorofluoro-N,6-dimethylpyrimidinamine (50.9 mg, 0.29 mmol, 1.00 equiv), trifluoroacetic acid (98.5 mg, 0.87 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at 80 oC in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by prep-HPLC; mobile phase, water (0.05%TFA) and ACN (5.0% ACN up to 73.0% in 7 min), or, UV 254/220 nm. This resulted in 78.6 mg (54%) of the title compound as a light yellow solid.

Example 15: Synthesis of Compound 33 Synthesis of 2-N-[3-(1H-indolyl)methoxyphenyl]N,6-dimethylpyrimidine-2,4- diamine hydrochloride: Synthesis of 2-N-[3-(1H-indolyl)methoxyphenyl]N,6-dimethylpyrimidine-2,4- Into a 30-mL round-bottom flask was placed 2-N-(3-iodomethoxyphenyl)N,6- dimethylpyrimidine-2,4-diamine (300 mg, 0.81 mmol, 1.00 equiv), dioxane (10 mL), water(3 mL), potassium carbonate (336 mg, 2.43 mmol, 3.00 equiv), Pd(dppf)Cl2CH2Cl2 (66 mg), and 4- (tetramethyl-1,3,2-dioxaborolanyl)-1H-indole (295 mg, 1.21 mmol, 1.50 equiv). The resulting on was stirred for 3 h at 80 oC. The crude product was purified by prep-HPLC; Mobile Phase A:Water/0.05%HCl, Mobile Phase B: ACN. This resulted in 44.1 mg (14%) of the title compound as a solid.

Attorney Docket No.: EPIZ-073/001WO 2-2509) Example 16: Synthesis of Compound 35 Synthesis of 2-N-(4-methoxy[1H-pyrazolo[4,3-c]pyridinyl]phenyl)N,6- dimethylpyrimidine-2,4-diamine; trifluoroacetic acid: Synthesis (4-methoxy[1H-pyrazolo[4,3-c]pyridinyl]phenyl)N,6- dimethylpyrimidine-2,4-diamine: Into a 30-mL round-bottom flask was placed 2-N-(3-iodomethoxyphenyl)N,6- dimethylpyrimidine-2,4-diamine (300 mg, 0.81 mmol, 1.00 equiv), DMSO (4 mL), CuI (61 mg, 0.32 mmol, 0.40 equiv), K3PO4 (516 mg, 2.43 mmol, 3.00 equiv), 1H-pyrazolo[4,3-c]pyridine (385 mg, 3.23 mmol, 3.99 equiv), and 1-N,2-N-dimethylcyclohexane-1,2-diamine (92 mg, 0.65 mmol, 0.80 equiv). The resulting solution was stirred for 12 h at 120 oC. The crude product was ed by prep-HPLC; Mobile Phase A:Water/0.05%TFA, Mobile Phase B: ACN. This resulted in 102.7 mg (27%) of the title compound as a white solid.

Example 17: Synthesis of Compound 36 Synthesis of 2-N-(4-methoxy[1H-pyrrolo[2,3-c]pyridinyl]phenyl)N,6- dimethylpyrimidine-2,4-diamine: N NH N O N N N O N H N H N N N N I N N N CuI,K3PO4,DMSO H H Synthesis of 2-N-(4-methoxy[1H-pyrrolo[2,3-c]pyridinyl]phenyl)N,6- dimethylpyrimidine-2,4-diamine: Into a 20-mL vial purged and maintained with an inert atmosphere of nitrogen was placed 1H-pyrrolo[2,3-c]pyridine (289 mg, 2.45 mmol, 3.02 , CuI (61.6 mg, 0.32 mmol, 0.40 equiv), K3PO4 (516 mg, 2.43 mmol, 3.00 , DMSO (5 mL), 2-N-(3-iodomethoxyphenyl)- ey Docket No.: EPIZ-073/001WO (311622-2509) 4-N,6-dimethylpyrimidine-2,4-diamine (300 mg, 0.81 mmol, 1.00 equiv), and (1R,2R)N,2-N- dimethylcyclohexane-1,2-diamine (92.1 mg, 0.65 mmol, 0.80 equiv). The resulting solution was stirred for 1 overnight at 100 oC. The crude product was purified by Prep-HPLC; mobile phase, mmol/L NH4HCO3) and ACN (25.0% ACN up to 31.0% in 12 min), detector, UV 254/220 nm. This resulted in 114.5 mg (39%) of the title compound as a white solid.

Example 18: Synthesis of Compound 37 Synthesis of 2-N-[3-(1H-indazolyl)methoxyphenyl]N,6-dimethylpyrimidine- 2,4-diamine; trifluoroacetic acid: Synthesis of 2-N-[3-(1H-indazolyl)methoxyphenyl]N,6-dimethylpyrimidine-2,4- diamine: Into a 20-mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed 2-N-(3-iodomethoxyphenyl)N,6-dimethylpyrimidine-2,4-diamine (200 mg, 0.54 mmol, 1.00 , 4-(tetramethyl-1,3,2-dioxaborolanyl)-1H-indazole (224 mg, 0.92 mmol, 1.70 equiv), potassium carbonate (224 mg, 1.62 mmol, 3.00 equiv), dioxane (10 mL), 2 mL), and Pd(dppf)Cl2CH2Cl2 (49 mg, 0.07 mmol, 0.10 equiv). The resulting solution was d for 1 overnight at 80 oC in an oil bath, then concentrated under vacuum. The resulting on was extracted with 3x80 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x50 mL of water and 2x50 mL of Brine. The mixture was dried over ous sodium sulfate. The resulting mixture was concentrated under vacuum. The crude product was purified by prep-HPLC; mobile phase, Mobile Phase A:Water/0.05% TFA, Mobile Phase B: ACN; detector, 254 nm. This resulted in 37.8 mg (15%) of the title compound as an off-white solid.

Example 19: Synthesis of Compound 56 Attorney Docket No.: EPIZ-073/001WO (311622-2509) Synthesis of N2-(4-methoxy(4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine hydrochloride: Synthesis of N2-(4-methoxy(4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Into a 25-mL round-bottom flask, was placed tert-butyl 2-(2-methoxy((4-methyl (methylamino)pyrimidinyl)amino)phenyl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridine carboxylate (100 mg, 0.21 mmol, 1.00 equiv), trifluoroacetic acid (73 mg, 0.65 mmol, 3.00 equiv), and romethane (5 mL). The resulting solution was stirred for 24 h at 25 oC. The resulting e was concentrated under vacuum. The residue was applied onto a silica gel column with H2O (0.05% TFA):ACN (1:1). This resulted in 16.1 mg (9%) of the title compounds as a light yellow solid.

Example 20: Synthesis of Compound 108 Synthesis of N2-(4-methoxy(4-((methylamino)methyl)-1H-pyrazolyl)phenyl)- imethylpyrimidine-2,4-diamine N NH O H Cl N N N O N NH I NH2 I N N H CuI NH NH O OH O N N N N N N N N H H O N NaBH3CN NH N Step 1: Synthesis of 2-N-(3-iodomethoxyphenyl)N,6-dimethylpyrimidine-2,4- Into a 500-mL round-bottom flask, was placed 3-iodomethoxyaniline (20 g, 80.31 mmol, 1.00 , IPA (240 mL), trifluoroacetic acid (17.6 g, 155.70 mmol, 2.00 equiv), 2- chloro-N,6-dimethylpyrimidinamine (12.7 g, 80.58 mmol, 1.00 equiv). The resulting solution Attorney Docket No.: EPIZ-073/001WO 2-2509) was stirred for 2 h at room temperature. The solids were collected by filtration. This resulted in 26 g (87%) of the title compound as a brown solid. ical Data: LC-MS: (ES, m/z): RT = 1.058 min; : m/z = 371 [M+1]. 2.

Step 2: Synthesis of 1-(2-methoxy[[4-methyl(methylamino)pyrimidin yl]amino]phenyl)-1H-pyrazolecarbaldehyde Into a 50-mL bottom flask, was placed 2-N-(3-iodomethoxyphenyl)N,6- dimethylpyrimidine-2,4-diamine (1 g, 2.70 mmol, 1.00 equiv), Tol (10 mL), CuI (154 mg, 0.81 mmol, 0.30 , K3PO4 (1.72 g, 8.10 mmol, 3.00 equiv), azolecarbaldehyde (262 mg, 2.73 mmol, 1.00 equiv), (1R,2R)N,2-N-dimethylcyclohexane-1,2-diamine (230 mg, 1.62 mmol, 0.60 equiv). The resulting solution was stirred for 24 h at 140oC. The residue was d onto a silica gel column with water/ACN (1:50-1:10). The collected fractions were combined and concentrated under vacuum. This resulted in 550 mg (60%) of the title compound as an off-white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.981 min; LCMS33: m/z = 339 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 9.91 (s, 1H), 8.77 (d, J = 0.6 Hz, 1H), 8.38 (s, 1H), 8.16 (s, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.17 (d, J = 9.0 Hz, 1H), 5.82 (s, 1H), 3.91 (s, 3H), 2.89 (s, 3H), 2.18 (s, Step 3: Synthesis of N2-(4-methoxy(4-((methylamino)methyl)-1H-pyrazol yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine Into a 25-mL round-bottom flask, was placed 1-(2-methoxy[[4-methyl (methylamino)pyrimidinyl]amino]phenyl)-1H-pyrazolecarbaldehyde (140 mg, 0.41 mmol, 1.00 equiv), NaBH3CN (5 g, 79.57 mmol, 192.30 equiv), methanol (233 mg, 7.27 mmol, 6.00 , methanamine (104 mg, 3.35 mmol, 4.00 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLCSHIMADZU (HPLC-10)): Column, XSelect CSH Prep C18 OBD Column,, 19*250mm,5um; mobile phase, Water(0.05%TFA ) and ACN (10.0% ACN up to 30.0% in 7 min); Detector, uv 254/220nm. This resulted in 47.5 mg (25%) of the title compound as a trifluoroacetic acid salt as a white solid.

Example 21: Synthesis of Compound 109 Attorney Docket No.: EPIZ-073/001WO (311622-2509) Synthesis of N2-(3-(4-((dimethylamino)methyl)-1H-pyrazolyl)methoxyphenyl)- N4,6-dimethylpyrimidine-2,4-diamine: Step 1: Synthesis of N2-(3-(4-((dimethylamino)methyl)-1H-pyrazolyl) methoxyphenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Into a 25-mL round-bottom flask, was placed 1-(2-methoxy[[4-methyl (methylamino)pyrimidinyl]amino]phenyl)-1H-pyrazolecarbaldehyde (160 mg, 0.47 mmol, 1.00 equiv), NaBH3CN (5 g, 79.57 mmol, 168.27 equiv), methanol (240 mg, 7.49 mmol, 4.00 equiv), dimethylamine (119 mg, 2.64 mmol, 4.00 equiv). The resulting solution was stirred for 2 h at room ature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLCSHIMADZU (HPLC-10)): Column, t CSH Prep C18 OBD Column, mm,5um; mobile phase, Water(0.05%TFA ) and ACN (15.0% ACN up to 35.0% in 7 min); or, uv 254/220nm. This resulted in 89.2 mg (39%) of the title compound as the trifluoroacetic acid salt as a white solid.

Example 22: Synthesis of Compound 113: sis of N2-(4-methoxy(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Step 1: Synthesis of tert-butyl 1-(2-methoxy[[4-methyl(methylamino)pyrimidin yl]amino]phenyl)-1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridinecarboxylate: Attorney Docket No.: EPIZ-073/001WO (311622-2509) Into a 100-mL round-bottom flask, was placed tert-butyl (3E) [(dimethylamino)methylidene]oxopiperidinecarboxylate (500 mg, 1.87 mmol, 1.00 equiv), AcOH (225 mg, 3.75 mmol, 2.00 equiv), methanol (10 mL), 2-N-(3-hydrazinyl methoxyphenyl)N,6-dimethylpyrimidine-2,4-diamine (580 mg, 1.87 mmol, 1.00 equiv). The resulting solution was stirred for 15 h at 65 oC in an oil bath. The resulting mixture was concentrated under vacuum. The e was d onto a silica gel column with H2O (0.05% TFA):ACN (1:1). This resulted in 300 mg (26%) of as a yellow oil.

Analytical Data: LC-MS: (ES, m/z): RT = 1.18 min, LCMS 33: m/z = 466 [M+1].

Step 2: Synthesis of N2-(4-methoxy(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom flask, was placed tert-butyl ethoxy[[4-methyl (methylamino)pyrimidinyl]amino]phenyl)-1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine carboxylate (300 mg, 0.64 mmol, 1.00 , trifluoroacetic acid (290 mg, 1.92 mmol, 3.00 equiv), dichloromethane (10 mL). The resulting solution was d for 24 h at 25 oC. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with 05%NH4HCO3):ACN (3:1). This resulted in 16.5 mg (7%) of the title compound as a light yellow solid.

Example 23: Synthesis of Compound 137: Synthesis of N2-(4-methoxy(4-(pyrrolidinyl)-1H-1,2,3-triazolyl)phenyl)-N4,6- dimethylpyrimidine-2,4-diamine: Step 1: Synthesis of tert-butyl 2-[1-(2-methoxynitrophenyl)-1H-1,2,3-triazol yl]pyrrolidinecarboxylate: Into a 100-mL round-bottom flask, was placed 2-azidomethoxynitrobenzene (1 g, .15 mmol, 1.00 equiv), tert-butanol (10 mL), water(20 mL), dioxo(sulfonylidene)copper (80 mg, Attorney Docket No.: EPIZ-073/001WO (311622-2509) 0.50 mmol, 0.10 equiv), tert-butyl nylpyrrolidinecarboxylate (1.1 g, 5.53 mmol, 1.10 equiv). The resulting solution was stirred for 3 h at 80 oC in an oil bath. The resulting solution was ted with 20 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 550 mg (25%) of the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.12 min, LCMS 53: m/z = 390 [M+1].

Step 2: Synthesis of tert-butyl 2-[1-(5-aminomethoxyphenyl)-1H-1,2,3-triazol yl]pyrrolidinecarboxylate: Into a 25-mL round-bottom flask, was placed utyl 2-[1-(2-methoxynitrophenyl)- 1H-1,2,3-triazolyl]pyrrolidinecarboxylate (50 mg, 0.13 mmol, 1.00 equiv), palladium carbon (10 mg), ethyl acetate (2 mL). The resulting solution was stirred for 12 h at 25 oC. The solids were filtered out. The resulting mixture was trated under vacuum. This resulted in 30 mg (62%) of the title compound as a yellow solid. ical Data: LC-MS: (ES, m/z): RT = 1.02 min, LCMS 33: m/z = 360 [M+1].

Step 3: sis of tert-butyl 2-[1-(2-methoxy[[4-methyl(methylamino)pyrimidin- 2-yl]amino]phenyl)-1H-1,2,3-triazolyl]pyrrolidinecarboxylate: Into a 50-mL round-bottom flask, was placed tert-butyl 2-[1-(5-aminomethoxyphenyl)- 1H-1,2,3-triazolyl]pyrrolidinecarboxylate (400 mg, 1.21 mmol, 1.00 equiv), trifluoroacetic acid (400 mg, 3.64 mmol, 3.00 equiv), IPA (10 mL), 2-chloro-N,6-dimethylpyrimidinamine (174 mg, 1.20 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at 80 oC in an oil bath.

The solids were collected by filtration. The resulting mixture was concentrated under vacuum.

This resulted in 200 mg (36%) of the title compound as a pink solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.32 min, LCMS 27: m/z = 481 [M+1].

Step 4: Synthesis of tert-butyl 2-methoxynitrophenyl)-1H-1,2,3-triazol yl]pyrrolidinecarboxylate: Into a 50-mL bottom flask, was placed tert-butyl 2-[1-(2-methoxy[[4-methyl (methylamino)pyrimidinyl]amino]phenyl)-1H-1,2,3-triazolyl]pyrrolidinecarboxylate (200 mg, 0.42 mmol, 1.00 equiv), trifluoroacetic acid (200 mg, 1.27 mmol, 3.00 equiv), dichloromethane (8 mL). The resulting solution was stirred for 24 h at 25 oC. The resulting mixture was trated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XSelect CSH Prep C18 OBD Column,, 5um,19*150mm; mobile phase, Water (0.05% TFA ) and ACN (5.0% ACN Attorney Docket No.: EPIZ-073/001WO (311622-2509) up to 20.0% in 8 min); Detector, UV 254/220nm. This resulted in 21.8 mg of the title compound as the trifluoroacetic acid salt as a white solid.

Example 24: sis of Compound 157: Synthesis of N2-(4-methoxy(1H-pyrrolo[2,3-c]pyridinyl)phenyl)-N4,6- dimethylpyrimidine-2,4-diamine: I I O NHBoc NH2 NO2 NHBoc NO2 Boc2O, EtONa, N N 3)2Cl2,CuI N DMAP THF, 65oC F F NH O O N O O OH N NO2 Pd/C NH2 Cl N N H N N NH EA NH 80oC H TFA,IPA NH N N N Step 1: Synthesis of utyl N-(4-iodopyridinyl)carbamate: Into a 100-mL round-bottom flask, was placed 4-iodopyridinamine (2 g, 9.09 mmol, 1.00 equiv), Boc2O (2.4 g, 11.00 mmol, 1.21 equiv), 4-dimethylaminopyridine (1 g, 8.19 mmol, 0.90 equiv), dichloromethane (50 mL). The resulting solution was stirred for 1 overnight at room temperature. The resulting solution was extracted with of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1: 10).This resulted in 1.9 g (65%) of the title compound as an offwhite solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.719min, LCMS45: m/z =321 [M+1].

Step 2: Synthesis of tert-butyl N-[4-[2-(2-methoxynitrophenyl)ethynyl]pyridin yl]carbamate Into a 50-mL round-bottom flask purged and maintained with an inert here of nitrogen, was placed tert-butyl N-(4-iodopyridinyl)carbamate (700 mg, 2.19 mmol, 1.00 equiv), Pd(PPh3)2Cl2 (144 mg, 0.21 mmol, 0.09 equiv), CuI (83 mg, 0.44 mmol, 0.20 equiv), TEA (1.1 g, .87 mmol, 4.97 equiv), DMSO (5 mL), [2-(2-methoxynitrophenyl)ethynyl]trimethylsilane (544 mg, 2.18 mmol, 1.00 . The resulting solution was stirred for 4 h at 50 oC. The resulting solution was ted with of ethyl acetate and the organic layers ed. This resulted in 420 mg (52%) of the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT 0.880= min, LCMS45: m/z = 370 [M+1].

Attorney Docket No.: EPIZ-073/001WO 2-2509) Step 3: Synthesis of 2-(2-methoxynitrophenyl)-1H-pyrrolo[2,3-c]pyridine: Into a 10-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-[4-[2-(2-methoxynitrophenyl)ethynyl]pyridinyl]carbamate (30 mg, 0.08 mmol, 1.00 equiv), EtONa (11 mg), ethanol (2 mL). The final reaction mixture was irradiated with ave radiation for 2 h at 65 oC. The crude product was used in the next reaction without further purification. ical Data: LC-MS: (ES, m/z): RT =1.715 min, LCMS30: m/z = 270 [M+1].

Step 4: Synthesis of 4-methoxy[1H-pyrrolo[2,3-c]pyridinyl]aniline: Into a 50-mL 3-necked round-bottom flask, was placed 2-(2-methoxynitrophenyl)-1H- pyrrolo[2,3-c]pyridine (109 mg, 0.40 mmol, 1.00 equiv), ethyl acetate (20 mL), Palladium carbon (30 mg), hydrogen. The resulting solution was stirred for 1 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 100 mg of the title compound as a brown solid.

Analytical Data: LC-MS: (ES, m/z): RT = 1.041min, LCMS31: m/z = 270 [M+1].

Step 5: Synthesis of N2-(4-methoxy(1H-pyrrolo[2,3-c]pyridinyl)phenyl)-N4,6- ylpyrimidine-2,4-diamine: Into a 40-mL vial, was placed 4-methoxy[1H-pyrrolo[2,3-c]pyridinyl]aniline (100 mg, 0.42 mmol, 1.00 equiv), IPA (15 mL, 1.09 , oroacetic acid (156 mg, 1.38 mmol, 3.30 equiv), 2-chloro-N,6-dimethylpyrimidinamine (71.6 mg, 0.45 mmol, 3.30 . The resulting solution was stirred for 3 h at 80 oC in an oil bath. The crude product (100 g) was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC- )): Column, XSelect CSH Prep C18 OBD Column,, 19*250mm,5um; mobile phase, Water (0.05%TFA ) and ACN (10.0% ACN up to 35.0% in 7 min); Detector, UV 254/220nm. 19.2 mg product was obtained and concentrated under vacuum. This ed in 19.2 mg (10%) of the title compound as the trifluoroacetic acid salt as an off-white solid.

Example 25: Synthesis of Compound 159: Synthesis of N2-(4-methoxy(4-((methylamino)methyl)-1H-1,2,3-triazol yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine: ey Docket No.: EPIZ-073/001WO (311622-2509) Step 1: Synthesis of [1-(2-methoxy[[4-methyl(methylamino)pyrimidin yl]amino]phenyl)-1H-1,2,3-triazolyl]methanol: Into a 50-mL round-bottom flask, was placed 1-(2-methoxy[[4-methyl (methylamino)pyrimidinyl]amino]phenyl)-1H-1,2,3-triazolecarboxylic acid (700 mg, 1.97 mmol, 1.00 equiv), BH3/THF (15 mL). The resulting solution was stirred for 20 h at 20 oC. The resulting mixture was concentrated under vacuum. The on was then quenched by the addition of 5 mL of. The residue was applied onto a silica gel column with methanol/H2O(0.05% TFA) (1/1). This resulted in 350 mg (52%) of the title compound as an off-white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.856 min; : m/z = 342 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.42 – 8.28 (m, 2H), 7.58 (d, J = 9.0 Hz, 1H), 7.33 (d, J = 9.0 Hz, 1H), 6.01 (q, J = 0.9 Hz, 1H), 4.78 (d, J = 0.7 Hz, 2H), 3.96 (s, 3H), 3.01 (s, 3H), 2.44 – 2.28 (m, 3H).

Step 2: Synthesis of 2-N-[3-[4-(chloromethyl)-1H-1,2,3-triazolyl]methoxyphenyl]- 4-N,6-dimethylpyrimidine-2,4-diamine: Into a 100-mL round-bottom flask, was placed [1-(2-methoxy[[4-methyl (methylamino)pyrimidinyl]amino]phenyl)-1H-1,2,3-triazolyl]methanol (200 mg, 0.59 mmol, 1.00 equiv), dichloromethane (40 mL), thionyl chloride (346 mg, 5.00 equiv), N,N- ylformamide (2 drop). The resulting solution was stirred for 1 h at 20 oC. The ing solution was diluted with 30 mL of H2O. The resulting solution was ted with 3x80 mL of dichloromethane and the organic layers combined and concentrated under vacuum. This resulted in 137 mg (65%) of the title compound as an off-white solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.994 min; LCMS15: m/z = 360 [M+1].

Attorney Docket No.: EPIZ-073/001WO (311622-2509) Step 3: Synthesis of N2-(4-methoxy(4-((methylamino)methyl)-1H-1,2,3-triazol yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom flask, was placed 2-N-[3-[4-(chloromethyl)-1H-1,2,3-triazol- 1-yl]methoxyphenyl]N,6-dimethylpyrimidine-2,4-diamine (137 mg, 0.38 mmol, 1.00 equiv), methanamine hydrochloride (127 mg, 1.88 mmol, 5.00 equiv), potassium carbonate (420 mg, 3.04 mmol, 8.00 equiv), ACN (15 mL). The resulting solution was stirred for 2 days at 20 oC. The solids were ed out. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLCSHIMADZU (HPLC-10)): Column, XSelect CSH Prep C18 OBD Column,, 5um,19*150mm; mobile phase, Water (0.05% TFA ) and ACN (5.0% ACN up to 20.0% in 7 min); or, UV 254/220nm. This resulted in 62.8 mg (35%) of the title compound as the trifluoroacetic acid salt as a white solid.

Example 26: Synthesis of nd 175: Synthesis of N2-(4-methoxy(1H-pyrrolo[3,2-c]pyridinyl)phenyl)-N4- methylpyrimidine-2,4-diamine: Step 1: sis of 6-(2-methoxynitrophenyl)-1H-pyrrolo[3,2-c]pyridine: Into a 30-mL vial purged and ined with an inert atmosphere of nitrogen, was placed ro-1H-pyrrolo[3,2-c]pyridine (500 mg, 3.28 mmol, 1.00 equiv), 2-(2-methoxy nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.1 g, 3.94 mmol, 1.20 equiv), Pd(dppf)Cl2 (270 mg, 0.37 mmol, 0.11 equiv), potassium carbonate (1.36 g, 9.84 mmol, 3.00 equiv), Dioxane (10 mL), water(1 mL). The resulting solution was stirred for 4 h at 80 oC in an oil bath. The resulting on was extracted with 3x30 mL of ethyl acetate and the organic layers combined.

Attorney Docket No.: EPIZ-073/001WO 2-2509) The residue was d onto a silica gel column with ethyl acetate/petroleum ether (60%). This resulted in 280 mg (crude) of the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.543 min, LCMS30: m/z = 270 [M+1].

Step 2: Synthesis of oxy[1H-pyrrolo[3,2-c]pyridinyl]aniline: Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of H2, was placed 6-(2-methoxynitrophenyl)-1H-pyrrolo[3,2-c]pyridine (280 mg, 1.04 mmol, 1.00 equiv), methanol (5 mL), Palladium on carbon (190 mg). The resulting solution was stirred for 2 h at 20 oC. The solids were filtered out. This resulted in 190 mg (76%) of the title compound as a brown solid.

Analytical Data: LC-MS: (ES, m/z): RT = 0.702 min, LCMS15: m/z = 240 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.82 (d, J = 1.1 Hz, 1H), 7.74 (t, J = 1.0 Hz, 1H), 7.41 (d, J = 3.2 Hz, 1H), 7.32 (s, 1H), 7.04 (d, J = 2.8 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 6.67 (s, 1H), 3.75 (s, 3H).

Step 3: Synthesis of N2-(4-methoxy(1H-pyrrolo[3,2-c]pyridinyl)phenyl)-N4- pyrimidine-2,4-diamine: Into a 50-mL round-bottom flask, was placed 4-methoxy[1H-pyrrolo[3,2-c]pyridin yl]aniline (180 mg, 0.75 mmol, 1.00 equiv), 2-chloro-N-methylpyrimidinamine (107 mg, 0.75 mmol, 0.99 , trifluoroacetic acid (171.7 mg, 1.52 mmol, 2.02 equiv), IPA (5 mL). The resulting on was stirred for 2 h at 80 oC in an oil bath. The crude product was purified by Prep-HPLC with the following conditions :Column: X Select C18, 19*250 mm, 5 um; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 25% B to 64% B in 15min. This resulted in 67.8 mg (20%) of the title compound as the trifluoroacetic acid salt as a white solid.

Example 27: Synthesis of Compound 181: Synthesis of N2-(4-methoxy(4-((methylamino)methyl)-1H-pyrazolyl)phenyl)- N4-methylpyrimidine-2,4-diamine: NH NH O O N NaBH3CN,MeOH,HOAc N N N N N N N H HCl H N NH N ey Docket No.: 73/001WO (311622-2509) Step 1: Synthesis of N2-(4-methoxy(4-((methylamino)methyl)-1H-pyrazol yl)phenyl)-N4-methylpyrimidine-2,4-diamine: Into a 25-mL round-bottom flask, was placed ethoxy[[4- (methylamino)pyrimidinyl]amino]phenyl)-1H-pyrazolecarbaldehyde (80 mg, 0.25 mmol, 1.00 equiv), methanol (2 mL), amine (34 mg, 1.09 mmol, 2.00 equiv) and stirred for 15min. Then NaBH3CN (93 mg, 1.48 mmol, 6.00 equiv), acetic acid (0.002 mL). The resulting solution was stirred for 2 h at 25 oC. The crude product was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XSelect CSH Prep C18 OBD , 5um,19*150mm; mobile phase, CH3CN: Water (0.05% HCl ) = 1/9; Detector, UV 0nm. This resulted in 36.6 mg (37%) of the title compound as the hydrochloride salt as a white solid.

Example 28: Synthesis of Compound 200: Synthesis of N2-(4-methoxy(3-methyl-1H-pyrrolo[2,3-c]pyridinyl)phenyl)-N4,6- dimethylpyrimidine-2,4-diamine: Step 1: Synthesis of 1-methoxynitro(propynyl)benzene: Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-iodomethoxynitrobenzene (2.8 g, 10.03 mmol, 1.00 , tributyl(propynyl)stannane (5 g, 15.19 mmol, 1.51 equiv), Pd(PPh3)2Cl2 (200 mg, 0.28 mmol, 0.03 equiv), dioxane (30 mL). The resulting solution was stirred overnight at 80 oC. The solids were filtered out. The resulting solution was extracted with of ethyl acetate and the organic layers combined. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (5%). This resulted in 1.06 g (55%) of the title compound.

Step 2: Synthesis of 2-(2-methoxynitrophenyl)methyl-1H-pyrrolo[2,3-c]pyridine: Attorney Docket No.: EPIZ-073/001WO (311622-2509) Into a 20-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed 1-methoxynitro(propynyl)benzene (500 mg, 2.62 mmol, 1.00 equiv), 4-iodopyridin amine (1.1 g, 5.00 mmol, 1.91 equiv), )2 (110 mg, 0.49 mmol, 0.19 equiv), KOAc (750 mg, 7.64 mmol, 2.92 equiv), LiCl (0.11 g), N,N-dimethylformamide (10 mL). The resulting solution was d overnight at 100 oC. The crude product was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, mobile phase, Detector, Xbridge C18 OBD 19*150mm. This ed in 167 mg (23%) of the title compound.

Step 3: Synthesis of 4-methoxy(3-methyl-1H-pyrrolo[2,3-c]pyridinyl)aniline: Into a 20-mL vial, was placed 2-(2-methoxynitrophenyl)methyl-1H-pyrrolo[2,3- c]pyridine (150 mg, 0.53 mmol, 1.00 equiv), Zn (300 mg), AcOH (8 mL). The resulting solution was stirred for 2 h at 25 oC. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 115 mg (86%) of the title compound as a yellow solid.

Step 4: sis of N2-(4-methoxy(3-methyl-1H-pyrrolo[2,3-c]pyridinyl)phenyl)- N4,6-dimethylpyrimidine-2,4-diamine: Into a 20-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed 4-methoxy[3-methyl-1H-pyrrolo[2,3-c]pyridinyl]aniline (100 mg, 0.39 mmol, 1.00 , 2-chloro-N,6-dimethylpyrimidinamine (50 g, 317.26 mmol, 803.61 equiv), trifluoroacetic acid (150 g, 1.33 mol, 3361.19 , IPA (8 mL). The resulting solution was stirred for 1 h at 80 oC.

The resulting mixture was concentrated under vacuum. This resulted in 22 mg (11%) of the title compound as the trifluoroacetyl fluoride salt.

Example 29: Synthesis of Compound 206: Synthesis of N2-(4-methoxy(1H-pyrrolo[3,2-c]pyridinyl)phenyl)-N4,6- ylpyrimidine-2,4-diamine: Step 1: Synthesis of 6-chlorotosyl-1H-pyrrolo[3,2-c]pyridine: ey Docket No.: EPIZ-073/001WO (311622-2509) Into a 50-mL round-bottom flask, was placed 6-chloro-1H-pyrrolo[3,2-c]pyridine (500 mg, 3.28 mmol, 1.00 equiv), tetrahydrofuran (20 mL), sodium hydride (473 mg, 19.71 mmol, 6.00 equiv), 4-methylbenzenesulfonyl chloride (937 mg, 4.91 mmol, 1.50 equiv). The resulting solution was stirred for 4 h at 80 oC. The ing solution was extracted with 200 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 900 mg (crude) of the title compound that was used without further purification.

Step 2: Synthesis of 6-(2-methoxynitrophenyl)tosyl-1H-pyrrolo[3,2-c]pyridine: Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of en, was placed ro[(4-methylbenzene)sulfonyl]-1H-pyrrolo[3,2-c]pyridine (500 mg, 1.63 mmol, 1.00 equiv), ethoxynitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1094.1 mg, 3.92 mmol, 2.40 equiv), Pd(dppf)Cl2 (676.5 mg, 0.92 mmol, 3.00 equiv), potassium carbonate (133.3 mg, 0.96 mmol, 0.10 equiv), water(20 mL), dioxane (2 mL). The resulting solution was stirred for 3 h at 80 oC. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl e/petroleum ether (2:3). This resulted in 600 mg (crude) of the title compound.

Step 3: Synthesis of 4-methoxy(1-tosyl-1H-pyrrolo[3,2-c]pyridinyl)aniline: Into a 50-mL vial, was placed 6-(2-methoxynitrophenyl)[(4- methylbenzene)sulfonyl]-1H-pyrrolo[3,2-c]pyridine (400 mg, 0.94 mmol, 1.00 equiv), Palladium carbon (200 mg), ol (20 mL), hydrogen. The resulting solution was stirred for 2 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum.

This resulted in 250 mg ) of the title compound.

Step 4: Synthesis of N2-(4-methoxy(1-tosyl-1H-pyrrolo[3,2-c]pyridinyl)phenyl)- N4,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom flask, was placed 4-methoxy[1-[(4- methylbenzene)sulfonyl]-1H-pyrrolo[3,2-c]pyridinyl]aniline (200 mg, 0.51 mmol, 1.00 equiv), 2-chloro-N,6-dimethylpyrimidinamine (80 mg, 0.51 mmol, 1.00 equiv), trifluoroacetic acid (147 mg, 1.30 mmol, 2.00 equiv), IPA (10 mL). The ing solution was stirred for 5 h at 80 oC.

The resulting mixture was concentrated under vacuum. This resulted in 250 mg (96%) of the title compound.

Step 5: Synthesis of N2-(4-methoxy(1H-pyrrolo[3,2-c]pyridinyl)phenyl)-N4,6- dimethylpyrimidine-2,4-diamine: Attorney Docket No.: EPIZ-073/001WO (311622-2509) Into a 50-mL round-bottom flask, was placed -methoxy[1-[(4- methylbenzene)sulfonyl]-1H-pyrrolo[3,2-c]pyridinyl]phenyl)N,6-dimethylpyrimidine-2,4- diamine (200 mg, 0.39 mmol, 1.00 equiv), sodium hydroxide (156 mg, 3.90 mmol, 10.00 equiv), ethanol (20 mL). The resulting solution was stirred for 3 h at 80 oC. The resulting mixture was trated under vacuum. The residue was applied onto a silica gel column with ethyl e/petroleum ether (1:1). The crude product was purified by PLC with the following conditions alyseHPLC-SHIMADZU(HPLC-10)): , XBridge Shield RP18 OBD Column, 30*150mm,5um; mobile phase, Water(10 mmol/L NH4HCO3) and ACN (30.0% ACN up to 43.0% in 7 min); Detector, UV 254220nm. This resulted in 24 mg (17%) of the title nd as a white solid.

Example 30: Synthesis of Compound 212: Synthesis of (S)-N2-(4-methoxy(4-(pyrrolidinyl)-1H-1,2,3-triazolyl)phenyl)- N4,6-dimethylpyrimidine-2,4-diamine: Step 1: Synthesis of tert-butyl (S)(1-(2-methoxy((4-methyl (methylamino)pyrimidinyl)amino)phenyl)-1H-1,2,3-triazolyl)pyrrolidinecarboxylate: Into a 20-mL vial, was placed tert-butyl (S)(1-(5-aminomethoxyphenyl)-1H-1,2,3- triazolyl)pyrrolidinecarboxylate (prepared as for compound 137 starting with tert-butyl (S)- 2-ethynylpyrrolidinecarboxylate, 1 g, 2.78 mmol, 1.00 equiv), 2-chloro-N,6- dimethylpyrimidinamine (525 mg, 3.33 mmol, 1.20 equiv), trifluoroacetic acid (958 mg, 8.47 mmol, 3.05 equiv), IPA (9 mL). The resulting solution was stirred for 1 h at 80 oC. The solids were collected by filtration. This resulted in 800 mg (60%) of title compound.

Step 2: Synthesis of (S)-N2-(4-methoxy(4-(pyrrolidinyl)-1H-1,2,3-triazol yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Attorney Docket No.: EPIZ-073/001WO (311622-2509) Into a 20-mL vial, was placed tert-butyl (2S)[1-(2-methoxy[[4-methyl lamino)pyrimidinyl]amino]phenyl)-1H-1,2,3-triazolyl]pyrrolidinecarboxylate (200 mg, 0.42 mmol, 1.00 equiv), trifluoroacetic acid (3 mL), dichloromethane (3 mL). The resulting solution was stirred for 1 h at 25 oC. The resulting mixture was trated under vacuum. This resulted in 57.8 mg (37%) of the title compound.

Synthesis of nd 238 sis of hoxy-N-methyl-6'-(3-methyl-1H-pyrrolo[2,3-c]pyridin yl)spiro[cyclobutane-1,3'-indol]-2'-amine: Step 1: sis of 5'-methoxy-N-methyl-6'-(propynyl)spiro[cyclobutane-1,3'- indol]-2'-amine: Into a 20-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed 6-romoethoxy-N-methylspiro[cyclobutane-1,3-ndole]amine (300 mg, 1.02 mmol, 1.00 equiv), Pd(PPh3)2Cl2 (142 mg, 0.20 mmol, 0.20 equiv), dioxane (8 mL), tributyl(propyn yl)stannane (500 mg, 1.52 mmol, 1.49 equiv). The ing solution was stirred overnight at 80 oC. The resulting solution was extracted with of ethyl acetate and the organic layers combined.

The residue was applied onto a silica gel column with ethyl acetate/hexane (30%). This resulted in 193 mg (75%) of the title compound.

Step 2: Synthesis of hoxy-N-methyl-6'-(3-methyl-1H-pyrrolo[2,3-c]pyridin yl)spiro[cyclobutane-1,3'-indol]-2'-amine: Into a 20-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed -ethoxy-N-methylpropynyl)spiro[cyclobutane-1,3-ndole]mine (50 mg, 0.20 mmol, 1.00 equiv), Pd2(dba)3 (40 mg, 0.04 mmol, 0.22 equiv), Ad2(n-Bu)P (38 mg), K3PO4 (80 mg, 0.38 mmol, 1.92 equiv), dioxane (5 mL), 4-iodopyridinamine (90 mg, 0.41 mmol, 2.08 equiv). The resulting solution was stirred overnight at 120 oC. The resulting solution was extracted with of ethyl acetate and the organic layers combined. This resulted in 29.7 mg (33%) of the title compound as the trifluoroacetic acid salt as a yellow solid.

Attorney Docket No.: EPIZ-073/001WO (311622-2509) Synthesis of Compound 262: Synthesis of N2-(4-chloro(4-((methylamino)methyl)-1H-pyrazolyl)phenyl)-N4,6- dimethylpyrimidine-2,4-diamine: Step 1: 1. Synthesis of (2-chloronitrophenyl)hydrazine: Into a 250-mL round-bottom flask, was placed 2-chloronitroaniline (3 g, 17.38 mmol, 1.00 , hydrogen de (60 mL), NaNO2 (1.5 g, 21.74 mmol, 1.25 equiv), SnCl2 (10 g, 52.74 mmol, 3.03 equiv). The resulting solution was stirred for 1.5 h at 0 oC in an ice/salt bath.

The solids were collected by filtration. This resulted in 8 g (crude) of the title compound as a yellow solid.

Step 2: Synthesis of ethyl 1-(2-chloronitrophenyl)-1H-pyrazolecarboxylate: Into a 100-mL round-bottom flask, was placed (2-chloronitrophenyl)hydrazine (1 g, .33 mmol, 1.00 , ethanol (40 mL), methyl 2-formyloxopropanoate (760 mg, 5.34 mmol, 1.00 equiv). The final reaction mixture was irradiated with microwave radiation for 2 h at 80 oC.

The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 600 mg ) of the title nd that was used without further purification.

Analytical Data: 1H NMR (300 MHz, Methanol-d4) δ 8.69 (d, J = 0.6 Hz, 1H), 8.52 (d, J = 2.6 Hz, 1H), 8.39 (q, J = 2.7 Hz, 1H), 8.20 (d, J = 0.6 Hz, 1H), 7.95 (d, J = 8.7 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H).

Step 3: Synthesis of ethyl 1-(5-aminochlorophenyl)-1H-pyrazolecarboxylate: Into a 100-mL round-bottom flask, was placed ethyl 1-(2-chloronitrophenyl)-1H- pyrazolecarboxylate (900 mg, 3.04 mmol, 1.00 equiv), Fe (900 mg, 5.00 equiv), NH4Cl (900 mg, 15.13 mmol, 5.00 equiv), ethanol/H2O (15 mL). The resulting solution was stirred for 2 h at 80 oC in an oil bath. The solids were ed out. The residue was applied onto a silica gel column with H2O (0.05%NH4HCO3):ACN (1:1). This resulted in 600 mg (67%) of the title compound.

Attorney Docket No.: EPIZ-073/001WO (311622-2509) Step 4: Synthesis of ethyl 1-(2-chloro((4-methyl(methylamino)pyrimidin yl)amino)phenyl)-1H-pyrazolecarboxylate: Into a 100-mL round-bottom flask, was placed ethyl 1-(5-aminochlorophenyl)-1H- pyrazolecarboxylate (532 mg, 2.00 mmol, 1.00 equiv), trifluoroacetic acid (458 mg, 4.05 mmol, 2.00 equiv), IPA (15 mL), 2-chloro-N,6-dimethylpyrimidinamine (316 mg, 2.01 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at 60 oC in an oil bath. The solids were ted by filtration. The resulting mixture was concentrated under vacuum. This ed in 500 mg (61%) of the title compound as a light yellow Step 5: Synthesis of (1-(2-chloro((4-methyl(methylamino)pyrimidin yl)amino)phenyl)-1H-pyrazolyl)methanol: Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 1-(2-chloro[[4-methyl(methylamino)pyrimidin yl]amino]phenyl)-1H-pyrazolecarboxylate (500 mg, 1.29 mmol, 1.00 equiv), LAH (450 mg, 11.86 mmol, 9.00 equiv), ydrofuran (30 mL). The ing on was stirred for 2 h at 25 oC. The reaction was then ed by the addition of. The resulting solution was extracted with 2x30 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 300 mg (61%) of the title compound.

Step 6: Synthesis of 1-(2-chloro((4-methyl(methylamino)pyrimidin yl)amino)phenyl)-1H-pyrazolecarbaldehyde: Into a 50-mL round-bottom flask, was placed [1-(2-chloro[[4-methyl lamino)pyrimidinyl]amino]phenyl)-1H-pyrazolyl]methanol (500 mg, 1.45 mmol, 1.00 equiv), MnO2 (500 mg, 5.75 mmol, 3.97 equiv), dichloromethane (10 mL). The resulting solution was d for 14 h at 40 oC in an oil bath. The solids were filtered out. The ing mixture was concentrated under vacuum. This resulted in 300 mg (54%) of the title compound.

Step 7: Synthesis of N2-(4-chloro(4-((methylamino)methyl)-1H-pyrazolyl)phenyl)- N4,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom flask, was placed 1-(2-chloro[[4-methyl (methylamino)pyrimidinyl]amino]phenyl)-1H-pyrazolecarbaldehyde (300 mg, 0.88 mmol, 1.00 equiv), NaBH3CN (150 mg, 2.59 mmol, 3.00 equiv), methanol (10 mL), AcOH (0.01 mL), methanamine (300 mg, 4.46 mmol, 5.00 equiv). The resulting solution was stirred for 12 h at 25 oC. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, Attorney Docket No.: EPIZ-073/001WO (311622-2509) XSelect CSH Prep C18 OBD Column,, 5um,19*150mm; mobile phase, Water(0.05%TFA ) and ACN (5.0% ACN up to 15.0% in 12 min); Detector, UV 254220nm. This resulted in 88.8 mg (22%) of the title compound as the oroacetic acid salt as a white solid.

Synthesis of Compound 286: Synthesis of N4,6-dimethyl-N2-(4-methyl(4-((methylamino)methyl)-1H-pyrazol yl)phenyl)pyrimidine-2,4-diamine: NH NH N NH N Boc N N N TFA/DCM N N N PO4,DMSO H N N N I N N H N N H H NH N N Boc Step 1: Synthesis of tert-butyl methyl((1-(2-methyl((4-methyl (methylamino)pyrimidinyl)amino)phenyl)-1H-pyrazolyl)methyl)carbamate: Into a 20-mL sealed tube, was placed 2-N-(3-iodomethylphenyl)N,6- dimethylpyrimidine-2,4-diamine (100 mg, 0.28 mmol, 1.00 equiv), tert-butyl N-methyl-N-(1H- pyrrolylmethyl)carbamate (62 mg, 0.29 mmol, 1.04 equiv), CuI (11 mg, 0.06 mmol, 0.20 , K3PO4 (178 mg, 0.84 mmol, 2.97 equiv), methyl[2-(methylamino)ethyl]amine (10 mg, 0.11 mmol, 0.40 equiv), DMSO (8 mL). The resulting solution was stirred ght at 120 oC.

The resulting solution was diluted with of H2O. The resulting solution was extracted with of ethyl acetate and the organic layers combined. The resulting mixture was washed with H2O. The mixture was dried over anhydrous sodium sulfate and concentrated under . This resulted in 100 mg (81%) of the title compound.

Analytical Data: LC-MS: (ES, m/z): RT=0.815 min, m/z =438 [M+1].

Step 2: Synthesis of N4,6-dimethyl-N2-(4-methyl(4-((methylamino)methyl)-1H- lyl)phenyl)pyrimidine-2,4-diamine: Into a 25-mL round-bottom flask, was placed utyl N-methyl-N-[[1-(2-methyl[[4- methyl(methylamino)pyrimidinyl]amino]phenyl)-1H-pyrrolyl]methyl]carbamate (100 mg, 0.23 mmol, 1.00 equiv), trifluoroacetic acid (1 mL), dichloromethane (5 mL). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#- AnalyseHPLC-SHIMADZU(HPLC-10)): , XSelect CSH Prep C18 OBD Column,, Attorney Docket No.: EPIZ-073/001WO (311622-2509) 5um,19*150mm; mobile phase, Water(0.05%TFA ) and ACN (5.0% ACN up to 23.0% in 12 min); Detector, UV 254/220nm. This resulted in 41.7 mg (40%) of the title compound as the trifluoroacetic acid salt as light yellow oil. sis of Compound 317: Synthesis of N2-(2-fluoromethoxy(4-((methylamino)methyl)-1H-pyrazol yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Step 1: Synthesis of ethyl 1-(2,6-difluorophenyl)-1H-pyrazolecarboxylate: Into a 100-mL round-bottom flask, was placed ifluorophenyl)hydrazine (1 g, 6.94 mmol, 1.00 equiv), ethanol (12 mL), ethyl 2-formyloxopropanoate (1.2 g, 8.33 mmol, 1.20 . The resulting solution was stirred for 2h at 50 oC in an oil bath. The t was removed under vacuum. The residue was applied onto a silica gel column with PE/EA = 50/1. The collected fractions were combined and concentrated under vacuum. This resulted in 1.18 g (67%) of the title compound.

Analytical Data: LC-MS: (ES, m/z): RT = 1.269 min; LCMS53: m/z = 253 [M+1]+ Step 2: Synthesis of ethyl 1-(2,6-difluoronitrophenyl)-1H-pyrazolecarboxylate: Into a 50-mL 3-necked round-bottom flask, was placed ethyl 1-(2,6-difluorophenyl)-1H- pyrazolecarboxylate (1.1 g, 4.36 mmol, 1.00 equiv), H2SO4 (5 mL), HNO3 (2 mL) was added dropwise at 0 oC with a water/ice bath. The resulting solution was stirred for 4 h at 25 oC. The resulting solution was extracted with 3x20 mL of ethyl acetate and the organic layers combined.

Dried over anhydrous Na2SO4 , concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA = 3/1. The ted fractions were ed and concentrated under vacuum. This resulted in 1 g (77%) of the title compound.

Analytical Data: LC-MS: (ES, m/z): RT = 1.264 min; LCMS15: m/z = 298[M+1]+ Attorney Docket No.: EPIZ-073/001WO (311622-2509) Step 3: Synthesis of ethyl 1-(2-fluoromethoxynitrophenyl)-1H-pyrazole ylate: Into a 100-mL round-bottom flask, was placed ethyl 1-(2,6-difluoronitrophenyl)-1H- pyrazolecarboxylate (1 g, 3.36 mmol, 1.00 equiv), methanol (20 mL), sodium methoxide in methanol solution (m/z = 35%, 0.5 ml, 1.0 equiv) was added dropwise at 0 oC,. The resulting solution was stirred for 2 h at 0oC. Then the resulting mixture was quenched by NH4Cl (aq) 10ml, extracted by EA 20 ml*3, dried over anhydrous Na2SO4, concentrated under . The e was applied onto a silica gel column with PE/EA = 10/1. The collected fractions were combined and concentrated under . This resulted in 500 mg (48%) of the title compound as yellow Step 4: Synthesis of ethyl 1-(3-aminofluoromethoxyphenyl)-1H-pyrazole carboxylate: Into a 50-mL round-bottom flask, was placed ethyl 1-(2-fluoromethoxynitrophenyl)- 1H-pyrazolecarboxylate (500 mg, 1.62 mmol, 1.00 , ethanol (10 mL), water (3 mL), Fe (453 mg, 8.08 mmol, 5 equiv), NH4Cl (857 mg, 16.02 mmol, 9.91 equiv). The resulting solution was stirred for 2 h at 80 oC in an oil bath. The solids were filtered out. The resulting solvent was concentrated under vacuum. The resulting was extracted with 3x20 mL of ethyl acetate and the organic layers combined, dried over anhydrous Na2SO4, concentrated under vacuum. This resulted in 400 mg (89%) of the title compound.

Step 5: Synthesis of ethyl 1-(2-fluoromethoxy((4-methyl (methylamino)pyrimidinyl)amino)phenyl)-1H-pyrazolecarboxylate: Into a 50-mL round-bottom flask, was placed ethyl 1-(3-aminofluoro methoxyphenyl)-1H-pyrazolecarboxylate (400 mg, 1.43 mmol, 1.00 equiv), ro-N,6- dimethylpyrimidinamine (270 mg, 1.71 mmol, 1.20 equiv), IPA (20 mL), trifluoroacetic acid (3 mL). The resulting on was stirred for 3 h at 80 oC in an oil bath. The resulting mixture was allowed to cooled to r.t. Then filtered, the solid was collected. This resulted in 500 mg (87%) of the title compound.

Step 6: Synthesis of (1-(2-fluoromethoxy((4-methyl(methylamino)pyrimidin yl)amino)phenyl)-1H-pyrazolyl)methanol: Into a 50-mL round-bottom flask, was placed ethyl 1-(2-fluoromethoxy[[4-methyl- hylamino)pyrimidinyl]amino]phenyl)-1H-pyrazolecarboxylate (400 mg, 1.00 mmol, 1.00 equiv), tetrahydrofuran (10 mL), LAH (114 mg, 3.00 mmol, 3.01 equiv) was added batch- Attorney Docket No.: EPIZ-073/001WO (311622-2509) wise. The ing solution was stirred for 1 h at 25 oC. The reaction was then quenched by the addition of 114 mg water. Then 114 mg NaOH (aq, m/z = 15%) and 342 mg water, 20 ml EA was added. Stirred at r.t. for 30 min. The solids were filtered out, the resulting solution was dried over anhydrous Na2SO4, concentrated under vacuum. This resulted in 300 mg (84%) of the title Step 7: Synthesis of luoromethoxy((4-methyl(methylamino)pyrimidin yl)amino)phenyl)-1H-pyrazolecarbaldehyde: Into a 50-mL round-bottom flask, was placed [1-(2-fluoromethoxy[[4-methyl lamino)pyrimidinyl]amino]phenyl)-1H-pyrazolyl]methanol (300 mg, 0.84 mmol, 1.00 equiv), chloroform (15 mL), MnO2 (730 mg, 8.40 mmol, 10.03 equiv). The resulting solution was stirred for 8 h at 70 oC in an oil bath. The solids were filtered out. The resulting mixture was concentrated under . This resulted in 200 mg (67%) of the title compound.

Step 8: Synthesis of N2-(2-fluoromethoxy(4-((methylamino)methyl)-1H-pyrazol yl)phenyl)-N4,6-dimethylpyrimidine-2,4-diamine: Into a 50-mL round-bottom flask, was placed 1-(2-fluoromethoxy[[4-methyl (methylamino)pyrimidinyl]amino]phenyl)-1H-pyrazolecarbaldehyde (100 mg, 0.28 mmol, 1.00 equiv), DCE (10 mL), methanamine (200 mg, 6.44 mmol, 22.95 , STAB (180 mg, 0.85 mmol, 3.03 equiv). The resulting solution was stirred for 2 h at 25 oC. The ing mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#SHIMADZU (HPLC-01)): Column, XBridge Prep C18 OBD Column, 19*150mm 5um; mobile phase, Water(0.05%TFA) and ACN (5.0% ACN up to 23.0% in 10 min); Detector, UV 220/254nm. This resulted in 66.5 mg (49%) of the title compound.

Other compounds were synthesized in the similar manner and the characterization data are listed in Table 2 below.

Table 2 Cpd Data 1 LC-MS: (ES, m/z): RT = 0.958 min, LCMS 33: m/z = 366 [M+1]. 1H-NMR: (400 MHz, Methanol-d4) δ 8.18 (s, 1H), 7.87 (s, 1H), 7.54 – 7.51 (m, 1H), 7.12 (d, J = 8.8 Hz, 1H), .82 (s, 1H), 4.02 (s, 2H), 3.86 (s, 3H), 3.24 (t, J = 6.0 Hz, 2H), 2.94 – 2.83 (m, 5H), 2.19 (s, 3H).

Attorney Docket No.: EPIZ-073/001WO (311622-2509) 2 LC-MS: (ES, m/z): RT = 1.504min, LCMS 33: m/z =380 [M+1]. 1H NMR: (400 MHz, Methanol-d4) δ 8.22 – 8.10 (m, 2H), 7.59 – 7.50 (m, 1H), 7.28 (d, J = 9.1 Hz, 1H), 6.02 (d, J = 1.2 Hz, 1H), 4.47 (s, 2H), 3.95 (s, 3H), 3.88 – 3.52 (m, 2H), 3.20 – 3.16(m, 2H), 3.10 (s, 3H), 3.03 (s, 3H), 2.32 (d, J = 2.4 Hz, 3H). 3 LC-MS: (ES, m/z): RT = 1.022 min, LCMS 33: m/z = 380.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.15 (d, J = 3.9 Hz, 2H), 7.53 (d, J = 2.7 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 6.02 (d, J = 0.8 Hz, 1H), 4.62 (s, 2H), 3.95 (s, 3H), 3.82 (s, 1H), 3.77 (s, 1H), 3.17 – 2.94 (m, 8H), 2.32 (d, J = 0.9 Hz, 3H). 4 LC-MS: (ES, m/z): RT=1.06min，LCMS28，m/z=394.2 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.26 (d, J = 2.5 Hz, 1H), 8.12 (d, J = 2.7 Hz, 1H), 7.74 – 7.65 (m, 1H), 7.26 (d, J = 9.0 Hz, 1H), 6.66 (d, J = 2.5 Hz, 1H), 5.99 (d, J = 1.1 Hz, 1H), 4.48 (s, 2H), 3.93 (d, J = 5.7 Hz, 3H), 3.65 (s, 2H), 3.30 (d, J = 7.4 Hz, 2H), 3.02 (s, 3H), 2.34 – 2.29 (m, 3H), 2.21 – 2.11 (m, 2H), 2.10 – 1.99 (m, 2H).

LC-MS: (ES, m/z): RT =1.020 min, LCMS28, m/z =394.2 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.20 (d, J = 2.7 Hz, 1H), 7.87 (s, 1H), 7.61 – 7.51 (m, 1H), 7.30 (d, J = 9.0 Hz, 1H), 6.02 (d, J = 1.2 Hz, 1H), 4.41 (s, 2H), 3.97 (s, 3H), 3.64 – 3.56 (m, 2H), 3.30 – 3.18 (m, 2H), 3.02 (s, 3H), 2.33 (d, J = 1.0 Hz, 3H), 2.20 (d, J = 7.9 Hz,2H), 2.12 – 2.01 (m, 2H). 6 LC-MS: (ES, m/z): RT = 0.963 min, LCMS27: m/z = 380.1 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.08 (d, J = 2.8 Hz, 1H), 7.54 (s, 2H), 6.98 (d, J = 8.9 Hz, 1H), 5.79 (d, J = 0.8 Hz, 1H), 4.12 (t, J = 5.7 Hz, 2H), 3.92 (s, 3H), 3.71 (s, 2H), 2.99 – 2.93 (m, 2H), 2.91 (d, J = 8.0 Hz, 3H), 2.54 (s, 3H), 2.18 (s, 3H). 7 LC-MS: (ES, m/z): RT = 0.901 min, LCMS15: m/z = 366.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.06 (d, J = 2.8 Hz, 1H), 7.56 – 7.53 (m, 2H), 6.98 (d, J = 8.9 Hz, 1H), 5.79 (d, J = 0.8 Hz, 1H), 4.07 – 4.03 (m, 4H), 3.91 (s, 3H), 3.28 – 3.18 (m, 2H), 2.89 (s, 3H), 2.18 (s, 3H). 8 LC-MS: (ES, m/z): RT = 2.985 min, LCMS 07: m/z = 367 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.23 (d, J = 2.7 Hz, 1H), 7.64 (d, J = 9.0, 2.8 Hz, 1H), 7.27 – 7.19 (m, 1H), 6.06 (d, J = 1.3 Hz, 1H), 4.74 (s, 2H), 4.63 (t, J = 5.7 Hz, 2H), 3.94 (d, J = 5.6 Hz, 5H), 2.99 (d, J = 3.1 Hz, 3H), 2.42 (s, 3H), 2.32 (s, 3H).

LC-MS: (ES, m/z): 96 min, LCMS 07, m/z=381 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.30 (d, J = 2.8 Hz, 1H), 7.61 (d, J = 9.0, 2.7 Hz, 1H), 7.21 (d, J = 9.1 Hz, 1H), 5.99 (d, J = 1.1 Hz, 1H), 4.64 – 4.52 (m, 4H), 3.93 (d, J = 7.8 Hz, 3H), 3.82 (d, J = 5.7 Hz, 2H), 3.11 (s, 3H), 3.02 (s, 3H), 2.31 (d, J = 0.9 Hz, 3H).

LC-MS: (ES, m/z): RT = 0.863 min, LCMS 07: m/z = 380 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 7.81 – 7.63 (m, 3H), 7.30 (d, J = 8.1 Hz, 1H), 6.01 (d, J = 1.2 Hz, 1H), 4.34 (s, 2H), 3.89 (s, 3H), 3.46 – 3.42 (m, 2H), 3.04 – 3.01 (m, 8H), 2.30 (s, 3H).

LC-MS: (ES, m/z): 39 min, LCMS 28, m/z=326 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.39 (d, J = 2.7 Hz, 1H), 7.75 (dd, J = 9.0, 2.7 Hz, 1H), 7.31 (dd, J = 16.7, 9.0 Hz, 1H), 6.04 (d, J = 1.2 Hz, 1H), 4.06 (s, 3H), 3.01 (s, 3H), 2.61 (s, 3H), 2.33 (s, 3H).

Attorney Docket No.: EPIZ-073/001WO (311622-2509) LC-MS: (ES, m/z): RT = 1.175 min; LCMS53: m/z = 311 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.03 (s, 2H), 7.92 (s, 1H), 7.48 (d, J = 8.8Hz, 1H), 6.99 (d, J = 8.9 Hz, 1H), 5.80 (s, 1H), 3.89 (s, 3H), 2.92 (s, 3H), 2.18 (s, 3H).

LC-MS: (ES, m/z): RT=1.531 min, LCMS28, 2 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.10 (d, J = 2.8 Hz, 1H), 7.58 (dd, J = 8.9, 2.7 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.58 (s, 1H), 6.01 (s, 1H), 3.96 (s, 3H), 3.01 (s, 3H), 2.32 (s, 3H), 2.225 – 2.137 (m, 1H), 1.181 – 1.116 (m, 2H), 1.06 – 0.94 (m, 2H).

LC-MS: (ES, m/z): RT = 1.463 min, LCMS07: m/z = 351 [M+1]. 1H NMR: (400 MHz, Methanol-d4): δ 8.23 – 7.98 (m, 1H), 7.83 – 7.77(m, 1H), 7.53 (d, J = 8.9, 1H), 7.45 (d, J = 0.8 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 5.80 (d, J = 0.8 Hz, 1H), 3.84 (s, 3H), 2.88 (s, 3H), 2.17 (s, 3H), 1.83 – 1.77 (m, 1H), 1.09 – 0.71 (m, 2H), 0.70 – 0.39 (m, 2H).

LC-MS: (ES, m/z): RT = 1.30 min, LCMS 28: m/z = 311 [M+1]. 1H NMR: (300 MHz, Methanol-d4) δ 8.21 – 8.12 (m, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.78 – 7.67 (m, 1H), 7.50 (dd, J = 8.9, 2.7 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 6.57 – 6.47 (m, 1H), 6.28 – 5.98 (m, 1H), 3.95 (s, 3H), 3.00 (s, 3H), 2.44 – 2.28 (m, 3H).

LC-MS: (ES, m/z): RT = 1.407 min, LCMS28: m/z = 367.1 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.53 (d, J = 2.5 Hz, 1H), 8.34 (d, J = 2.6 Hz, 1H), 7.54 (s, 1H), 5.85 (d, J = 0.8 Hz, 1H), 3.94 (d, J = 2.1 Hz, 5H), 3.12 (t, J = 5.9 Hz, 2H), 2.87 (s, 3H), 2.67 (t, J = 5.9 Hz, 2H), 2.19 (s, 3H).

LC-MS: (ES, m/z): RT = 0.834 min, LCMS 07: m/z = 367 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 7.89 – 7.76 (m, 2H), 7.31 (d, J = 15.3, 9.0 Hz, 1H), 6.06 (d, J = 1.3 Hz, 1H), 4.77 (d, J = 2.0 Hz, 2H), 4.34 (t, J = 5.7 Hz, 2H), 3.96 (d, J = 2.8 Hz, 3H), 3.78 (d, J = 6.5, 4.9 Hz, 2H), 2.99 (d, J = 4.5 Hz, 3H), 2.43 (d, J = 0.9 Hz, 1H), 2.33 (d, J = 1.0 Hz, 3H).

LC-MS: (ES, m/z): RT = 0.992min LCMS 33: m/z =366 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.18 – 8.07 (m, 2H), 7.50 (d, J = 9.0 Hz, 1H), 7.29 (d, J = 9.0 Hz, 1H), 6.04 (d, J = 1.2 Hz, 1H), 4.44 (d, J = 6.9 Hz, 2H), 3.95 (s, 3H), 3.55 (t, J = 6.3 Hz, 2H), 3.11 – 2.95 (m, 5H), 2.45 – 2.29 (m, 3H). 23 LC-MS: (ES, m/z): 63min，LCMS31，m/z=340.4 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.38 (d, J = 2.0 Hz, 1H), 8.16 (s, 1H), 7.81 (s, 1H), 7.55 (s, 1H), 7.29 (s, 1H), 6.02 (s, 1H), 4.16 (s, 2H), 3.96 (d, J = 1.6 Hz, 3H), 3.01 (d, J = 2.4 Hz, 3H), 2.32 (s, 3H). 24 LC-MS: (ES, m/z):RT = 1.357 min; LCMS07: m/z = 340 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 7.88 – 7.70 (m, 3H), 7.51 – 7.15 (m, 1H), 6.79 – , 1H), 6.21 (s, 1H), 4.10 (s, 2H), 3.89 (s, 3H), 2.86(s, 3H), 2.55 (s, 3H). 26 LC-MS: (ES, m/z): RT=2.978min, LCMS31, m/z=365.4[M+1]. 1H NMR (400 MHz, Methanol-d4) δ 7.70 – 7.58 (m, 2H), 7.45 (d, J = 5.0 Hz, 1H), 7.29 – 7.17 (m, 1H), 6.00 (d, J = 1.1 Hz, 1H), 3.85 (d, J = 5.1 Hz, 3H), 2.96 (d, J = 3.6 Hz, 3H), 2.64 – 2.57 (m, 2H), 2.51 – 2.44 (m, 2H), 2.31 (d, J = 1.0 Hz, 3H), 1.88 – 1.75 (m, 4H).

LC-MS: (ES, m/z): RT = 0.99min, LCMS28: m/z = 384.19 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.18 (s, 1H), 8.12 (d, J = 2.7 Hz, 1H), 7.51 (dd, J = 8.9, 2.8 Hz, 1H), 7.27 (d, J = 9.0 Hz, 1H), 4.39 (s, 2H), 3.95 (s, 3H), 3.62 (t, J = 6.3 Hz, 2H), 3.18 – 3.02 (m, 5H), 2.36 (d, J = 2.9 Hz, 3H).

Attorney Docket No.: EPIZ-073/001WO (311622-2509) LC-MS: (ES, m/z): RT = 0.99min, LCMS15: m/z = 384.19 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 7.77 – 7.71 (m, 2H), 7.68 (s, 1H), 7.35-7.2 (m, 1H), 4.36 (s, 2H), 3.89 (s, 3H), 3.55 (t, J = 6.2 Hz, 2H), 3.05 (s, 3H), 2.94 (t, J = 6.2 Hz, 2H), 2.37 (d, J = 2.9 Hz, 3H).

LC-MS: (ES, m/z): RT=0.929 MS28, m/z=380 [M+1]. 1H NMR (400 MHz, ol-d4) δ 8.00 (dd, J = 9.0, 2.7 Hz, 1H), 7.53 (d, J = 2.7 Hz, 1H), 7.27 (dd, J = .3, 9.1 Hz, 1H), 6.01 (d, J = 1.2 Hz, 1H), 4.90 – 4.73 (m, 2H), 4.35 – 4.23 (m, 1H), 4.20 – 4.05 (m, 1H), 3.89 (d, J = 5.1 Hz, 4H), 3.75 – 3.63 (m, 1H), 2.98 (d, J = 2.8 Hz, 3H), 2.35 – 2.27 (m, 6H).

LC-MS: (ES, m/z): RT=1.221 min, LCMS 07, 1 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.02 (d, J = 7.8 Hz, 1H), 7.93 (s, 1H), 7.81 (d, J = 8.2 Hz, 0H), 7.42 (d, J = 8.3 Hz, 1H), 6.07 (s, 1H), 5.05 – 4.99 (m, 3H), 4.64 (d, J = 12.0 Hz, 2H), 4.01 (d, J = 8.4 Hz, 6H), 3.28 (d, J = 5.0 Hz, 4H), 3.00 (s, 3H), 2.35 (s, 3H).

LC-MS: (ES, m/z): RT = 1.81 min, LCMS 33: m/z = 366.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 7.87 – 7.68 (m, 3H), 7.35 – 7.25 (m, 1H), 6.05 – 5.98 (m, 1H), 3.89 (s, 3H), 3.61 – 3.50 (m, 2H), 2.98 (s, 3H), 2.73 (t, J = 6.3 Hz, 2H), 2.32 (d, J = 1.2 Hz, 3H), 2.19 (d, J = 6.3 Hz, 2H).

LC-MS: (ES, m/z): RT=1.375min, LCMS15, m/z=360.2 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H), 11.16 (s, 1H), 10.22 (s, 1H), 8.92 (s, 1H), 7.63 – 7.52 (m, 2H), 7.43 – 7.29 (m, 2H), 7.25 – 7.07 (m, 2H), 7.04 – 6.95 (s, 1H), 6.20 (s, 1H), 6.01 (d, J = 1.2 Hz, 1H), 3.72 (s, 3H), 2.85 (d, J = 4.6 Hz, 3H), 2.25 (s, 3H).

LC-MS: (ES, m/z): RT=0.966min, LCMS15, m/z=362.2 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 9.58 (s, 1H), 8.93 – 8.88 (m, 1H), 8.56 (s, 1H), 8.11 – 8.05 (m, 1H), 7.88 – 7.75 (m, 2H), 7.42 (d, J = 9.1 Hz, 1H), 6.06 – 6.00 (m, 1H), 3.89 (s, 3H), 3.00 (s, 3H), 2.33 (d, J = 0.9 Hz, 3H).

LC-MS: (ES, m/z): RT=1.045 min, LCMS28, m/z=362 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.75 (d, J = 1.2 Hz, 1H), 8.38 (d, J = 0.8 Hz, 1H), 8.28 (d, J = 5.7 Hz, 1H), 8.16 (s, 1H), 7.87 (dd, J = 5.7, 1.3 Hz, 1H), 7.68 (dd, J = 9.0, 2.7 Hz, 1H), 7.23 (d, J = 9.1 Hz, 1H), 5.80 (s, 1H), 3.80 (s, 3H), 2.82 (s, 3H), 2.16 (s, 3H).

LC-MS: (ES, m/z): RT=1.274min LCMS 15, m/z =361 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 7.85 (s, 1H), 7.67 (d, J = 2.7 Hz, 1H), 7.62 – 7.39 (m, 3H), 7.26 – 7.13 (m, 2H), 5.98 (d, J = 1.3 Hz, 1H), 3.82 (s, 3H), 2.94 (s, 3H), 2.30 (s, 3H).

LC-MS: (ES, m/z): RT = 1.077 min, LCMS 07: m/z = 363 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 9.37 – 9.16 (m, 1H), 8.97 – 8.77 (m, 1H), 8.46 (d, J = 4.9, 2.7 Hz, 1H), 8.35 – 8.21 (m, 1H), 7.72 – 7.49 (m, 1H), 7.33 – 7.21 (m, 1H), 6.07 – 5.91 (m, 1H), 3.97 (d, J = 12.7, 5.6, 2.5 Hz, 3H), 2.98 (d, J = 17.2, 8.0, 4.1 Hz, 3H), 2.35 – 2.24 (m, 3H).

LC-MS: (ES, m/z): 58 min,LCMS45, m/z=376 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 9.35 (s, 1H), 8.27 (s, 2H), 8.02 (dd, J = 9.0, 2.7 Hz, 1H), 7.70 (d, J = 2.7 Hz, 1H), 7.37 (d, J = 9.1 Hz, 1H), 6.25 – 5.94 (m, 1H), 3.87 (d, J = 2.1 Hz, 3H), 2.96 (s, 3H), 2.60 (s, 3H), 2.46 – 2.23 (m, 3H).

LC-MS: (ES, m/z): RT = 1.028 min, LCMS 28: m/z = 361 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 9.75 (s, 1H), 9.69 (s, 1H), 8.67 (d, J = 2.7 Hz, 1H), 8.41 – 8.21(m, 1H), 8.12 (d, J = 7.0 Hz, 1H), 7.72 (dd, J = 9.1, 2.7 Hz, 1H), 7.46 (d, J = 9.1 Hz, 1H), 5.97 - 6.31 (m, 1H), 4.07 (s, 3H), 3.09 (s, 3H), 2.35 (d, J = 1.0 Hz, 3H).

LC-MS: (ES, m/z): RT=1.041 min,LCMS28, m/z=362 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 9.18 (t, J = 1.1 Hz, 1H), 8.82 (d, J = 1.0 Hz, 1H), 8.55 (s, 1H), 8.09 (d, J = 6.1 Hz, 1H), 7.77 (dd, J = 6.1, 1.4 Hz, 1H), 7.66 (dd, J = 9.0, 2.7 Hz, 1H), 7.23 (d, J = Attorney Docket No.: EPIZ-073/001WO (311622-2509) 9.1 Hz, 1H), 5.82 (d, J = 0.8 Hz, 1H), 3.91 (s, 3H), 2.91 (s, 3H), 2.18 (s, 3H).

LC-MS: (ES, m/z): RT = 0.847 min; LCMS48: m/z = 361 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.85 (s, 1H), 8.15 (s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.87 – 7.76 (m, 1H), 7.56 – 7.38 (m, 2H), 7.01 (d, J = 8.9 Hz, 1H), 6.88 (s, 1H), 6.55 – 6.41 (m, 1H), 5.74 (s, 1H), 3.75 (s, 3H), 2.81 (d, J = 4.5 Hz, 3H), 2.11 (s, 3H).

LC-MS: (ES, m/z): RT = 1.243 min; LCMS53: m/z = 367 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.14 (s, 1H), 7.82 (s, 1H), 7.52 – 7.50 (m, 1H), 7.13 (d, J = 9.0 Hz, 1H), .85 (d, J = 0.8 Hz, 1H), 4.76 (d, J = 1.0 Hz, 2H), 4.00 (t, J = 5.7 Hz, 2H), 3.86 (s, 3H), 2.95 – 2.92 (m, 3H), 2.88 – 2.80 (m, 2H), 2.20 (s, 3H).

LC-MS: (ES, m/z): RT = 0.911 min, LCMS15: m/z = 280 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.49 (s, 1H), 7.77 (s, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.20 – 7.10 (m, 2H), 6.90-6.85 (m, 1H), 5.82 (d, J = 1.2 Hz, 1H), 4.05 (s, 3H), 3.87 (s, 3H), 2.91 (s, 3H), 2.20 (s, 3H), 2.04 (s, 3H).

LC-MS: (ES, m/z): RT = 0.997 min; LCMS53: m/z = 362 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.91 (d, J = 1.0 Hz, 1H), 8.70 (d, J = 2.8 Hz, 1H), 8.32 (d, J = 5.7 Hz, 1H), 7.81 (d, J = 8.9 Hz, 1H), 7.68 (d, J = 5.6 Hz, 1H), 7.21 (d, J = 9.0 Hz, 1H), 5.84 (d, J = 0.8 Hz, 1H), 4.09 (s, 3H), 2.94 (s, 3H), 2.21 (s, 3H).

LC-MS: (ES, m/z): RT=1.092 min; m/z = 361 [M+1]. 1H NMR (300 MHz, Methanol- d4) δ 8.85 – 8.71 (m, 1H), 8.18 – 8.09 (m, 1H), 7.78 – 7.42 (m, 3H), 6.91 (d, J = 6.5 Hz, 2H), 5.66 (s, 1H), 3.86 (d, J = 2.3 Hz, 3H), 2.85 – 2.69 (m, 3H), 2.12 – 1.97 (m, 3H).

LC-MS: (ES, m/z):RT = 0.652 min; LCMS45: m/z = 367 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.73 (d, J = 2.5 Hz, 1H), 8.39 – 8.27 (m, 2H), 6.02 (d, J = 1.1 Hz, 1H), 4.38 (d, J = 1.1 Hz, 2H), 4.08 (s, 3H), 3.61 (t, J = 6.4 Hz, 2H), 3.11 (t, J = 6.3 Hz, 2H), 3.03 (s, 3H), 2.32 (s, 3H).

LC-MS: (ES, m/z): RT =0.397 min, LCMS53: m/z = 382 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 7.87 – 7.63 (m, 2H), 7.27 (d, J = 8.4 Hz, 1H), 6.01 (d, J = 1.2 Hz, 1H), 4.19 (d, J = 3.2 Hz, 2H), 3.87 (s, 3H), 3.83 – 3.42 (m, 2H), 3.11 (s, 5H), 2.98 (d, J = 2.7 Hz, 3H), 2.44 – 2.29 (m, 3H).

LC-MS: (ES, m/z): RT = 0.966min; LCMS 33: m/z =366 [M+1]. 1H NMR (300 MHz, ol-d4) δ 8.48 (s, 1H), 8.24 (d, J = 2.7 Hz, 1H), 7.52 (d, J = 2.7 Hz, 1H), 7.31 (d, J = 9.0 Hz, 1H), 6.05 (d, J = 0.9 Hz, 1H), 3.98 (s, 3H), 3.63 – 3.53 (m, 2H), 3.10 (s, 3H), 3.00 – 2.85 (m, 2H), 2.42 (s, 3H), 2.30 – 2.24 (m, 2H).

LC-MS: (ES, m/z): RT = 0.935 min, LCMS53: m/z = 381.3 [M+1]. 1H NMR (300 MHz, ol-d4) δ 8.67 (s, 1H), 8.35 (d, J = 2.6 Hz, 1H), 8.08 (s, 1H), 5.85 (d, J = 0.8 Hz, 1H), 4.02 (s, 3H), 3.74 (s, 2H), 3.06 – 2.88 (m, 7H), 2.61 (s, 3H), 2.20 (s, 3H).

LC-MS: (ES, m/z): RT =1.116 min, LCMS 28: m/z = 364 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 9.33 (d, J = 1.4 Hz, 1H), 8.96 – 8.88 (m, 2H), 8.47 (d, J = 2.8 Hz, 1H), 8.30 (d, J = 4.6 Hz, 1H), 6.06 (s, 1H), 4.14 (s, 3H), 3.03 (s, 3H), 2.34 (s, 3H).

LC-MS: (ES, m/z): RT=0.992 min,LCMS28, m/z=369 [M+1]. 1H-NMR: δ 9.08 (s, 1H), 8.24 (d, J = 2.7 Hz, 1H), 7.68 (dd, J = 9.0, 2.7 Hz, 1H), 7.34 (d, J = 9.1 Hz, 1H), 6.01 (q, J = 0.8 Hz, 1H), 4.54 (s, 2H), 4.00 (s, 3H), 3.02 (d, J = 3.4 Hz, 9H), 2.32 (d, J = 1.0 Hz, 3H).

LC-MS: (ES, m/z): RT = n, LCMS28: m/z = 370.17 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 9.25-9.2 (m, 1H), 8.81 – 8.57 (m, 1H), 8.54 – 8.35 (m, 1H), 6.34 – 6.00 (m, 1H), 4.60-4.55 (m, 2H), 4.16-4.13 (m, 3H), 3.05-2.96 (m, 9H), 2.57 – 2.26 (m, 3H).

Attorney Docket No.: EPIZ-073/001WO (311622-2509) LC-MS: (ES, m/z): RT = 1.412 min; LCMS07: m/z = 381 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.57 (s, 1H), 8.37 (s, 1H), 7.82 (s, 1H), 6.12 (s, 1H), 4.73 – 4.25 (m, 2H), 4.12 (s, 3H), 3.93 – 3.42 (m, 2H), 3.24 (t, J = 6.4 Hz, 2H), 3.18 – , 6H), 2.67 – 2.36 (m, 3H).

LC-MS: (ES, m/z): RT = 0.974 min, LCMS33: m/z = 369.3 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.71 (s, 1H), 8.37 (s, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.38 (d, J = 9.1 Hz, 1H), 6.03 (s, 1H), 4.58 (s, 2H), 3.99 (s, 3H), 3.08 – 2.99 (m, 9H), 2.34 (s, 3H).

LC-MS: (ES, m/z): RT=1.008 min,LCMS28, m/z=381 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 9.04 (s, 1H), 8.18 (d, J = 2.5 Hz, 1H), 7.75 (dd, J = 8.9, 2.3 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 6.02 (s, 1H), 4.62 (s, 2H), 4.36 (t, J = 8.2 Hz, 4H), 4.00 (s, 3H), 3.04 (s, 3H), 2.58 (s, 2H), 2.33 (s, 3H).

LC-MS: (ES, m/z): RT=1.766 min,LCMS28, m/z=399 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 9.05 (s, 1H), 8.18 (d, J = 2.6 Hz, 1H), 7.74 (dd, J = 9.0, 2.6 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 6.03 (d, J = 1.1 Hz, 1H), 5.63 – 5.30 (m, 1H), 4.81 – 4.66 (m, 4H), 4.59 – 4.46 (m, 2H), 4.00 (s, 3H), 3.04 (s, 3H), 2.33 (s, 3H).

LC-MS: (ES, m/z): RT = 0.933 min; LCMS07: m/z = 422 [M+1]. 1H NMR (300 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.35 (s, 1H), 7.86 (s, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.07 (d, J = 9.0 Hz, 1H), 6.92 (s, 1H), 5.75 (s, 1H), 4.60 (t, J = 6.5 Hz, 2H), 4.50 (t, J = 6.1 Hz, 2H), 3.78 (s, 3H), 3.65 (t, J = 6.4 Hz, 1H), 3.37 (s, 2H), 2.84 (d, J = 4.5 Hz, 3H), 2.70 (t, J = 5.7 Hz, 2H), 2.58 (t, J = 5.8 Hz, 2H), 2.10 (s, 3H).

LC-MS: (ES, m/z): RT= 0.999 min; LCMS33: m/z = 394 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.17 (s, 1H), 7.86 (s, 1H), 7.61 – 7.48 (m, 1H), 7.11 (d, J = 9.0 Hz, 1H), .82 (s, 1H), 3.85 (s, 3H), 3.73 (s, 2H), 3.26 – 2.82 (m, 7H), 2.82 – 2.7 (m, 2H), 2.18 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H).

LC-MS: (ES, m/z): RT = 1.663 min, LCMS15: m/z = 369.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.49 (s, 1H), 7.75 – 7.65 (m, 1H), 7.29 (d, J = 8.9 Hz, 1H), 6.05 – .98 (m, 1H), 4.49 (s, 2H), 4.08 (s, 3H), 3.01 (s, 9H), 2.32 (d, J = 0.9 Hz, 3H).

LC-MS: (ES, m/z): RT = 0.992 min; LCMS33: m/z = 369 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.86 – 8.52 (m, 2H), 8.49 – 8.19 (m, 1H), 8.05 – 7.73 (m, 1H), 6.15 – .79 (m, 1H), 4.34 (s, 2H), 4.11 (s, 3H), 3.02 (d, J = 5.1 Hz, 3H), 2.90 (s, 6H), 2.33 (d, J = 1.0 Hz, 3H).

LC-MS: (ES, m/z): RT = 1.161 min, LCMS 33: m/z = 408.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 7.74 – 7.70 (m, 2H), 7.58 – 7.50 (m, 1H), 7.33 – 7.28 (m, 1H), 6.01 (d, J = 2.4 Hz, 1H), 4.56 (d, J = 3.3 Hz, 2H), 3.96 – 3.75 (m, 5H), 2.97 (d, J = 7.2 Hz, 3H), 2.79 (t, J = 5.7 Hz, 2H), 2.32 (t, J = 5.8 Hz, 3H), 2.22 (s, 3H).

LC-MS: (ES, m/z): RT = 1.462 min; LCMS28: m/z = 382 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 7.73 – 7.61 (m, 3H), 7.45 –7.15 (m, 1H), 6.45 – 6.40 (m, 1H), 5.81(s, 1H), 4.24 (s, 2H), 3.95 (s, 3H), 2.97 (s, 3H), 2.44 (s, 3H),1.97 –1.73 (m, 3H).

LC-MS: (ES, m/z): RT=1.290 min, LCMS 07, 7 [M+1]. 1H-NMR (400 MHz, Methanol-d4) δ 7.87 – 7.75 (m, 2H), 7.22 (d, J = 9.2, 2.5 Hz, 1H), 5.98 – 5.97 (m, 0H), .96 (s, 1H), 4.868 (s, 2H), 3.98 (d, J = 6.2, 4.5 Hz, 2H), 3.93 – 3.82 (m, 5H), 2.94 (s, 3H), 2.27 (s, 3H), 1.54 (s, 10H).

LC-MS: (ES, m/z): 26 min,LCMS28, m/z=366 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.05 (d, J = 2.5 Hz, 1H), 7.94 – 7.69 (m, 1H), 7.34 (d, J = 9.1 Hz, 1H), 6.01 (d, J = 1.0 Hz, 1H), 4.42 (s, 2H), 4.07 (d, J = 5.9 Hz, 3H), 3.65 (t, J = 6.0 Hz, 2H), 3.13 (t, J = 6.0 Hz, 2H), 2.97 (s, 3H),2.32 (s, 3H).

Attorney Docket No.: EPIZ-073/001WO 2-2509) LC-MS: (ES, m/z): RT=0.923 min,LCMS28, m/z=380 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.07 (d, J = 2.6 Hz, 1H), 7.86 (dd, J = 9.0, 2.6 Hz, 1H), 7.33 (d, J = 9.1 Hz, 1H), 6.01 (d, J = 1.0 Hz, 1H), 4.50 (s, 2H), 4.07 (d, J = 5.8 Hz, 3H), 3.72 (t, J = 6.0 Hz, 2H), 3.16 (d, J = 14.2 Hz, 5H), 2.98 (d, J = 4.6 Hz, 3H), 2.32 (d, J = 1.0 Hz, 3H).

LC-MS: (ES, m/z): RT = 5.04 min, HPLC 07, m/z = 393.2 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 7.69 (d, J = 2.7 Hz, 1H), 7.50 (dd, J = 8.9, 2.7 Hz, 1H), 7.04 (d, J = 8.9 Hz, 1H), 6.47 (d, J = 1.1 Hz, 1H), 5.81 (d, J = 0.8 Hz, 1H), 3.74 (s, 3H), 3.49 (t, J = 1.5 Hz, 2H), 2.87 (s, 3H), 2.76 (t, J = 5.9 Hz, 2H), 2.61 (t, J = 5.9 Hz, 2H), 2.52 (s, 3H), 2.18 (s, 3H), 2.01 (d, J = 1.0 Hz, 3H).

LC-MS: (ES, m/z): RT = 1.045 min, LCMS33: m/z = 406.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.17 (s, 1H), 7.82 (s, 1H), 7.54 – 7.50 (m, 1H), 7.10 (d, J = 9.0 Hz, 1H), 5.80 (d, J = 0.8 Hz, 1H), 3.84 (s, 3H), 3.77 (d, J = 0.9 Hz, 2H), 3.06 (t, J = 6.0 Hz, 2H), 2.90 – 2.84 (m, 5H), 2.17 (s, 3H), 2.04 – 1.91 (m, 1H), 0.67 – 0.48 (m, 4H).

LC-MS: (ES, m/z): RT=1.021 min,LCMS28, m/z=380 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.29 (d, J = 2.8 Hz, 1H), 7.47 (dd, J = 8.9, 2.8 Hz, 1H), 7.13 (d, J = 8.9 Hz, 1H), 6.84 (s, 1H), 5.97 (s, 1H), 4.65 (s, 2H), 4.52 (t, J = 5.9 Hz, 2H), 3.92 (d, J = 3.6 Hz, 5H), 3.15 (s, 3H), 3.02 (s, 3H), 2.30 (s, 3H).

LC-MS: (ES, m/z): RT=1.015 min,LCMS28, m/z=366 [M+H]. 1H NMR (300 MHz, ol-d4) δ 8.25 (d, J = 2.8 Hz, 1H), 7.47 (dd, J = 8.9, 2.8 Hz, 1H), 7.18 – 7.07 (m, 1H), 6.85 (d, J = 1.0 Hz, 1H), 6.01 – 5.94 (m, 1H), 4.58 (d, J = 0.9 Hz, 2H), 4.53 – 4.43 (m, 2H), 3.93 (s, 3H), 3.88 – 3.79 (m, 2H), 3.02 (s, 3H), 2.29 (d, J = 1.0 Hz, 3H).

LC-MS: (ES, m/z): RT = 2.172 min, LCMS27: m/z = 426.1 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 9.16 (s, 1H), 8.51 (s, 1H), 8.32 (s, 1H), 5.94 (d, J = 0.8 Hz, 1H), 4.73 – 4.70 (m, 2H), 4.50 (t, J = 6.1 Hz, 2H), 4.07 (s, 3H), 3.78 – 3.70 (m, 4H), 2.35 (s, 7H), 2.21 (s, 3H).

LC-MS: (ES, m/z): RT =1.376 min, LCMS07: m/z = 451 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.17 (s, 1H), 7.84 (s, 1H),7.56 – 7.51(m, 1H) 7.11 (d, J = 9.0 Hz, 1H), .82 (s, 1H), 3.85 (s, 3H), 3.68 (d, J = 6.3 Hz, 2H), 3.59 (s, 2H), 2.95 – 2.80 (m, 4H), 2.64 (s, 3H), 2.51 (s, 3H), 2.44 – 2.40 (m, 2H), 2.16 (s, 3H).

LC-MS: (ES, m/z): RT = 1.24 min, LCMS 33: m/z = 492 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.20 – 8.13 (m, 2H), 7.39 – 7.38 (m, 1H), 7.27 (d, J = 9.0 Hz, 1H), 6.03 (d, J = 1.1 Hz, 1H), 4.62 (s, 1H), 4.34 (s, 1H), 3.94 (s, 3H), 3.82 (t, J = 8.2 Hz, 3H), 3.65 (d, J = 7.2 Hz, 2H), 3.52 (d, J = 5.4 Hz, 3H), 3.31 (s, 2H), 3.16 – 3.14 (m, 4H), 2.68 (s, 3H), 2.34 (d, J = 0.9 Hz, 3H).

LC-MS: (ES, m/z): RT=1.268 min,LCMS28, m/z=362 [M+H]. 1H NMR (300 MHz, DMSO-d6) δ 9.18 (d, J = 1.4 Hz, 1H), 8.93 (s, 1H), 8.81 – 8.66 (m, 2H), 7.88 (d, J = 4.7 Hz, 1H), 7.72 (d, J = 8.9 Hz, 1H), 7.41 (d, J = 1.0 Hz, 1H), 7.07 (d, J = 9.0 Hz, 1H), 6.96 (s, 1H), 5.76 (s, 1H), 3.89 (s, 3H), 2.91 (s, 3H), 2.12 (s, 3H).

LC-MS: (ES, m/z): RT=2.462 min, LCMS31, m/z=396 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.11 (d, J = 2.7 Hz, 1H), 7.91 (d, J = 14.9 Hz, 1H), 7.44 (dd, J = 8.9, 2.7 Hz, 1H), 7.24 (d, J = 8.9 Hz, 1H), 6.00 (d, J = 1.1 Hz, 1H), 4.43 (d, J = 6.6 Hz, 2H), 3.93 (d, J = 5.6 Hz, 3H), 3.00 (d, J = 15.7 Hz, 3H), 2.44 – 2.28 (m, 3H), 2.13 (d, J = 0.9 Hz, 3H), 1.99 (s, 3H).

LC-MS: (ES, m/z):RT = 1.113 min; LCMS07: m/z = 382 [M+1]. 1H-NMR (400 MHz, Methanol-d4) δ 8.19 – 8.05 (m, 2H), 7.49 – 7.39 (m, 1H), 7.51 – 7.13(m, 1H), 6.61 – 6.29 (m, 1H), 5.85 (s, 1H), 4.61 – 4.33 (m, 2H), 3.94 (s, 3H), 3.04 (s, 3H), 2.54 – 2.19 (m, 3H), 2.01 (s, 3H). ey Docket No.: EPIZ-073/001WO (311622-2509) LC-MS: (ES, T = 3.599 min; LCMS07: m/z = 396 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.23 – 8.06 (m, 2H), 7.57 – 7.43 (m, 1H), 7.45 – 7.06 (m, 1H), 6.48 – 6.36 (m, 1H), 5.87 (s, 1H), 4.63 (s, 2H), 3.97 – 3.89 (m, 3H), 3.21 – 2.87 (m, 6H), 2.51 – 2.17 (m, 6H).

LC-MS: RT= 1.04 min, LCMS 28: m/z = 376 [M+1]. 1H-NMR: (Methanol-d4, ppm): δ 9.83 (s, 1H), 8.66 (d, J = 2.7 Hz, 1H), 8.15 (d, J = 7.1 Hz, 1H), 7.95 (d, J = 7.1 Hz, 1H), 7.73 (dd, J = 9.0, 2.7 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 6.04 (s, 1H), 4.06 (s, 3H), 3.16 (s, 3H), 3.09 (s, 3H), 2.34 (d, J = 0.9 Hz, 3H).

LC-MS: (ES, m/z): RT= 2.13 min, LCMS 28: m/z = 392 [M+1]. 1H-NMR: (Methanol- d4, ppm): δ 9.09 (s, 1H), 8.46 (d, J = 2.7 Hz, 1H), 7.85 – 7.74 (m, 1H), 7.62 (dd, J = 9.0, 2.7 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 7.25 (dd, J = 6.6, 1.0 Hz, 1H), 6.02 (s, 1H), 4.25 (s, 3H), 4.01 (s, 3H), 3.05 (s, 3H), 2.33 (s, 3H).

LC-MS: (ES, m/z): RT=1.124 min, LCMS45, m/z=382 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.08 (s, 1H), 7.99 (s, 1H), 7.61 (dd, J = 8.9, 2.9 Hz, 1H), 7.27 (d, J = 9.0 Hz, 1H), 6.00 (s, 1H), 4.38 (s, 2H), 3.94 (s, 3H), 2.98 (d, J = 7.9 Hz, 9H), 2.31 (s, 3H), 2.22 (d, J = 0.8 Hz, 3H).

LC-MS: (ES, m/z): RT = 2.178 min, LCMS15: m/z = 382 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.58 (d, J = 6.0 Hz, 1H), 8.24 (d, J = 2.7 Hz, 1H), 7.47–7.42 (m, J = 5.1 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 6.03 (d, J = 1.2 Hz, 1H), 3.97 (d, J = 6.9 Hz, 3H), 3.03 (s, 3H), 2.88 (s, 3H), 2.49 (s, 3H), 2.32 (d, J = 0.9 Hz, 3H).

LC-MS: (ES, m/z): RT = 1.16min, LCMS33: m/z = 368.18 [M+1]. 1H NMR (400 MHz, ol-d4) δ 8.87-8.54 (m, 1H), 8.29 – 7.91 (m, 2H), 7.65-7.4 (m, 1H), 7.39- 7.12 (m, 1H), 6.35-5.65 (m, 1H), 4.12-3.85 (m, 3H), 2.95-3.18 (m, 3H), 2.92 (s, 3H), 2.49-2.25 (m, 3H).

LC-MS: (ES, m/z): RT = 0.11min, LCMS28: m/z = 396.21 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 7.89 (d, J = 2.7 Hz, 1H), 7.70 (dd, J = 9.0, 2.7 Hz, 1H), 7.14 (d, J = 9.1 Hz, 1H), 5.83 (d, J = 0.8 Hz, 1H), 3.80 (s, 3H), 2.92 (s, 3H), 2.87 (s, 3H), 2.39 (s, 3H), 2.26 (s, 3H), 2.19 (s, 3H).

LC-MS: (ES, m/z): RT=0.99min, LCMS28: m/z=382.23 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 7.85 (s, 1H), 7.70 (dd, J = 9.0, 2.8 Hz, 1H), 7.12 (d, J = 9.0 Hz, 1H), .82 (d, J = 0.8 Hz, 1H), 3.76 (d, J = 8.2 Hz, 5H), 2.86 (s, 3H), 2.52 (s, 3H), 2.30 (s, 3H), 2.17 (d, J = 7.9 Hz, 6H).

LC-MS: (ES, m/z): RT = 0.942 min; LCMS53: m/z = 354 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.40 (s, 1H), 8.25 – 8.15 (m, 1H), 7.81 (d, J = 0.7 Hz, 1H), 7.55 (d, J = 9.0 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 6.00 (d, J = 1.2 Hz, 1H), 4.21 (d, J = 2.1 Hz, 2H), 3.95 (s, 3H), 3.00 (s, 3H), 2.74 (s, 3H), 2.31 (s, 3H).

LC-MS: (ES, m/z): RT = 0.948; LCMS53: m/z = 368 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.46 (s, 1H), 8.21 (d, J = 2.6 Hz, 1H), 7.85 (s, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.29 (d, J = 8.9 Hz, 1H), 6.00 (d, J = 1.1 Hz, 1H), 4.34 (s, 2H), 3.95 (s, 3H), 3.01 (s, 3H), 2.90 (s, 6H), 2.31 (d, J = 0.9 Hz, 3H).

LC-MS: (ES, m/z): RT = 0.85 min, LCMS 27: m/z = 366.0 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 7.89 (d, J = 2.7 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.48 (s, 1H), 7.12 (d, J = 9.0 Hz, 1H), 5.81 (d, J = 0.8 Hz, 1H), 3.91 (s, 2H), 3.79 (s, 3H), 3.08 (t, J = 5.7 Hz, 2H), 2.86 (s, 3H), 2.61 (t, J = 5.7 Hz, 2H), 2.18 (s, 3H).

LC-MS: (ES, m/z): RT=1.637 min, LCMS28, m/z=397 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.40 (s, 1H), 8.04 (s, 1H), 7.50 (s, 1H), 6.74 (s, 1H), 4.16 – 4.07 (m, 2H), 3.99 (s, 3H), 3.83 – 3.72 (m, 4H), 3.47-3.53 (m, 1H), 3.01 (s, 3H), 2.36 (s, 6H), Attorney Docket No.: 73/001WO (311622-2509) 1.99 – 1.77 (m, 4H).

LC-MS: (ES, m/z): RT = 1.659 min; LCMS07: m/z = 369 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.74 (s, 1H), 8.49 (s, 1H), 7.64 (d, J =2.7 Hz, 1H), 7.12 (d, J = 9.0 Hz, 1H), 5.71 (s, 1H), 3.91 (s, 3H), 2.98 (s, 3H), 2.90 (s, 3H), 2.18 (s, 3H).

LC-MS: (ES, m/z): RT = 1.22 min, LCMS 33: m/z = 362 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.67 (d, J = 1.2 Hz, 1H), 8.54 – 8.45 (m, 1H), 8.04 – 7.88 (m, 2H), 7.75 – 7.51 (m, 2H), 7.37 (d, J = 9.3 Hz, 1H), 6.01 (q, J = 0.9 Hz, 1H), 3.87 (d, J = 5.7 Hz, 3H), 2.97 (d, J = 7.2 Hz, 3H), 2.32 (d, J = 1.2 Hz, 3H).

LC-MS: (ES, m/z): RT = 1.568 min, LCMS15: m/z = 381.2 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.64 (s, 1H), 8.36 (d, J = 2.6 Hz, 1H), 7.69 – 7.67 (m, 1H), 7.36 (d, J = 9.1 Hz, 1H), 6.03 (d, J = 1.2 Hz, 1H), 4.62 (s, 2H), 4.30 – 4.28 (m, 4H), 3.98 (s, 3H), 3.03 (s, 3H), 2.65 – 2.45 (m, 2H), 2.33 (s, 3H).

LC-MS: (ES, m/z): RT=0.912 min, LCMS 28, m/z =313.2 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.80 (s, 1H), 8.45 (s, 1H), 7.70 (s, 1H), 7.02 (s, 1H), 4.48 (s, 2H), 4.13 (s, 3H), 3.20 (s, 3H), 2.85 (s, 3H), 2.76 (s, 3H).

LC-MS: (ES, m/z): RT=0.957 min, LCMS 28, m/z =339.1 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.79 (s, 1H), 8.42 (s, 1H), 7.68 (s, 1H), 7.01 (s, 1H), 5.07 – 4.99 (m, 1H), 4.12 (s, 3H), 3.61 – 3.46 (m, 2H), 3.20 (s, 3H), 2.76 (s, 3H), 2.66 – 2.54 (m, 1H), 2.51 – 2.32 (m, 2H), 2.31 – 2.17 (m, 1H).

LC-MS: (ES, m/z): RT=2.426 min, , m/z=382 [M+1]. 1H NMR (300 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.85 (q, J = 4.6 Hz, 1H), 8.24 (d, J = 2.6 Hz, 1H), 8.84-8.87 (m, 1H), 7.98-7.95 (m, 1H), 7.46 (dd, J = 8.9, 2.7 Hz, 1H), 7.29 (d, J = 9.0 Hz, 1H), 6.02 (d, J = 1.1 Hz, 1H), 2.90 (d, J = 4.6 Hz, 3H), 2.74 (d, J = 4.7 Hz, 3H), 2.25 (s, 6H).

LC-MS: (ES, m/z): RT = 1.66 min, LCMS 15: m/z = 395.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.72 (s, 1H), 8.36 (d, J = 2.7 Hz, 1H), 7.69 (d, J = 2.7 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 6.03 (q, J = 0.9 Hz, 1H), 4.74 (t, J = 9.0 Hz, 1H), 3.98 (s, 4H), 3.40 (t, J = 9.6 Hz, 1H), 3.03 (d, J = 5.1 Hz, 6H), 2.75 – 2.51 (m, 2H), 2.33 (d, J = 0.9 Hz, 5H).

LC-MS: (ES, m/z): RT = 1.06 min, LCMS 33: m/z = 381 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.65 – 8.55 (m, 1H), 8.32 (d, J = 2.7 Hz, 1H), 7.80 – 7.60 (m, 1H), 7.36 (d, J = 9.0 Hz, 1H), 6.03 (q, J = 0.9 Hz, 1H), 5.04 – 4.92 (m, 1H), 3.96 (d, J = 7.2 Hz, 3H), 3.57 – 3.43 (m, 2H), 3.03 (s, 3H), 2.67 – 2.13 (m, 7H).

LC-MS: (ES, m/z): 10 min, LCMS 07, m/z=383 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.04 (s, 1H), 7.75 (d, J = 9.0, 2.8 Hz, 1H), 7.18 (d, J = 9.1 Hz, 1H), 5.83 (d, J = 0.7 Hz, 1H), 3.79 (s, 3H), 3.48 (s, 2H), 2.85 (s, 3H), 2.42 (s, 3H), 2.18 (s, 3H), 2.08 (s, 6H).

LC-MS: (ES, m/z): RT=0.976 min, LCMS 27, m/z=383 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.02 (s, 1H), 7.75 (d, J = 9.0, 2.8 Hz, 1H), 7.21 (d, J = 9.1 Hz, 1H), 5.83 (d, J = 0.8 Hz, 1H), 3.81 (s, 3H), 3.68 (s, 2H), 2.85 (s, 3H), 2.36 (s, 6H), 2.24 (s, 3H), 2.18 (s, 3H).

LC-MS: (ES, m/z): RT = 1.694 min; LCMS15: m/z = 397 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.42 (s, 1H), 8.30 (s, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.18 (d, J = 9.0 Hz, 1H), 5.82 (s, 1H), 3.88 (d, J = 5.7 Hz, 5H), 2.89 (s, 3H), 2.61 (q, J = 7.2 Hz, 4H), 2.18 (s, 3H), 1.16 (t, J = 7.2 Hz, 6H).

LC-MS: (ES, m/z): RT = 1.381 min, LCMS27: m/z = 375.0 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.57 (d, J = 1.0 Hz, 1H), 8.22 (d, J = 2.7 Hz, 1H), 7.63 – 7.46 (m, 3H), 7.34 (d, J = 9.0 Hz, 1H), 7.28 – 7.17 (m, 1H), 6.05 – 5.97 (m, 1H), 3.97 (s, 3H), 3.00 (s, 3H), 2.47 – 2.37 (m, 3H), 2.31 (d, J = 0.9 Hz, 3H).

Attorney Docket No.: EPIZ-073/001WO (311622-2509) LC-MS: (ES, m/z): RT = 2.711 min, LCMS33: m/z = 401.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.47 (d, J = 1.0 Hz, 1H), 8.37 (s, 1H), 7.63 – 7.60 (m, 1H), 7.56 – 7.53 (m, 1H), 7.45 (s, 1H), 7.19 (d, J = 9.0 Hz, 1H), 7.13 – 7.10 (m, 1H), 5.81 (s, 1H), 3.87 (s, 3H), 2.88 (s, 3H), 2.18 (s, 3H), 2.06 – 1.96 (m, 1H), 1.04 – 0.88 (m, 2H), 0.83 – 0.68 (m, 2H).

LC-MS: (ES, m/z): RT = 1.094 min, LCMS32: m/z = 361.3 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.73 (d, J = 1.0 Hz, 1H), 8.28 (d, J = 3.4 Hz, 1H), 7.78 – 7.75 (m, 1H), 7.75 – 7.53 (m, 2H), 7.45 – 7.29 (m, 2H), 7.14 – 7.12 (m, 1H), 6.03 (d, J = 1.2 Hz, 1H), 4.00 (s, 3H), 3.03 (s, 3H), 2.34 (d, J = 1.0 Hz, 3H).

LC-MS: (ES, m/z): RT = 1.737 min, LCMS33: m/z = 441.1 [M+1]. 1H-NMR: (CDCl3, ppm): 1H NMR (300 MHz, Methanol-d4) δ 8.74 (s, 1H), 8.33 (s, 1H), 8.00 (d, J = 3.0 Hz, 1H), 7.63 – 7.58 (m, 2H), 7.49 – 7.31 (m, 2H), 6.02 (s, 1H), 3.99 (s, 3H), 3.03 (s, 3H), 2.33 (s, 3H).

LC-MS: (ES, m/z): RT=1.085 min,LCMS28, m/z=376 [M+1]. 1H NMR (400 MHz, 6) δ 9.74 (s, 1H), 9.60 (s, 1H), 8.52 (d, J = 2.7 Hz, 1H), 8.24 – 8.12 (m, 1H), 7.61 (dd, J = 9.1, 2.8 Hz, 1H), 7.42 (d, J = 9.2 Hz, 1H), 6.03 (d, J = 1.2 Hz, 1H), 3.93 (s, 3H), 2.96 (s, 3H), 2.59 (s, 3H), 2.24 (s, 3H).

LC-MS: (ES, m/z): RT = 1.028 min; LCMS27: m/z = 375 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 7.76 (s, 1H), 7.65 (s, 1H), 7.58 – 7.46 (m, 2H), 7.54 – 7.23 (m, 1H), 7.18 – 6.89 (m, 1H), 5.80 (s, 1H), 3.78 (s, 3H), 2.90 (s, 3H), 2.60 (s, 3H), 2.19 (s, 3H).

LC-MS: (ES, m/z): RT=1.58min, : m/z=374.19 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 7.63 (d, J = 2.7 Hz, 1H), 7.50 – 7.31 (m, 3H), 7.19 – 7.00 (m, 2H), 6.29 – 5.75 (m, 1H), 3.88 – 3.78 (m, 3H), 3.02 – 2.91 (m, 3H), 2.5 – 2.36 (m, 3H), 2.28 (d, J = 1.0 Hz, 3H).

LC-MS: (ES, m/z): RT =1.125 min, LCMS28: m/z = 361 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.98 (s, 1H), 8.20 (d, J = 6.7 Hz, 2H), 8.08 (d, J = 6.5 Hz, 1H), 7.79 (d, J = 9.4 Hz, 1H), 7.45 – 7.33 (m, 2H), 6.05 (s, 1H), 4.14 (s, 3H), 3.00 (s, 3H), 2.35 (s, LC-MS: (ES, m/z): RT = 1.090 min; LCMS28: m/z = 375 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 9.14 (s, 1H), 8.42 (d, J = 6.8, 1.0 Hz, 1H), 8.08 (d, J = 6.8, 0.8 Hz, 1H), 7.85 (dd, J = 9.0, 2.7 Hz, 1H), 7.69 – 7.54 (m, 1H), 7.36 – 7.18 (m, 1H), 7.14 – 7.05 (m, 1H), 6.32 – 5.95 (m, 1H), 3.95 – 3.79 (m, 3H), 3.83 (s, 3H), 3.24 – 3.07 (m, 3H), 2.39 – 2.26 (m, 3H).

LC-MS: (ES, m/z): RT = 1.879 min; LCMS33: m/z = 355 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.62 (s, 1H), 8.38 – 8.31 (m, 1H), 7.67 (d, J = 9.1 Hz, 1H), 7.37 (d, J = 9.1 Hz, 1H), 6.06 – 6.01 (m, 1H), 4.45 (s, 2H), 3.98 (d, J = 0.8 Hz, 3H), 3.03 (s, 3H), 2.83 (s, 3H), 2.34 (d, J = 0.9 Hz, 3H).

LC-MS: (ES, m/z): RT = 1.420 min, LCMS 07: m/z = 382 [M+1]. 1H-NMR (400 MHz, Methanol-d4) δ 8.46 (s, 1H), 8.21 (d, J = 2.8 Hz, 1H), 7.50 – 7.46(m, 1H), 7.29 (d, J = 2.4 Hz, 1H), 6.04 (s, 1H), 4.32 (s, 2H), 3.98 (s, 3H), 3.05 (s, 3H), 2.92 (s, 6H), 2.44 – 2.31 (m, 6H).

LC-MS: (ES, m/z): RT=1.016 min,LCMS28, m/z=367 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.26 (d, J = 2.7 Hz, 1H), 7.50 – 7.40 (m, 1H), 7.19 – 7.03 (m, 2H), 5.99 (q, J = 0.7 Hz, 1H), 4.41 (d, J = 2.3 Hz, 2H), 3.96 (d, J = 9.6 Hz, 6H), 3.03 (s, 3H), 2.82 (s, 3H), 2.30 (s, 3H).

LC-MS: (ES, m/z): RT = 1.501 min; : m/z = 316 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.18 (s, 1H), 7.45 (s, 1H), 7.08 (d, J = 2.4 Hz, 1H), 4.01 (s, 0H), 3.88 (s, Attorney Docket No.: EPIZ-073/001WO (311622-2509) 3H), 3.73 (s, 2H), 3.57 (d, J = 1.3 Hz, 3H), 3.27 (s, 0H), 3.04 (s, 3H), 2.34 (s, 6H).

LC-MS: (ES, m/z): RT=0.932 min, LCMS27, m/z=369 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.43 (s, 1H), 8.28 (d, J = 1.7 Hz, 1H), 7.63 (dd, J = 9.0, 2.7 Hz, 1H), 7.20 (dd, J = 9.1, 2.9 Hz, 1H), 5.83 (d, J = 1.0 Hz, 1H), 3.98-4.03 (m, 1H), 3.90 (d, J = 1.8 Hz, 3H), 2.91 (s, 3H), 2.38 (d, J = 1.5 Hz, 3H), 2.19 (s, 3H), 1.53 (d, J = 6.8 Hz, LC-MS: RT = 1.077min; m/z= 423.2 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.77 (s, 1H), 8.36 (d, J = 2.6 Hz, 1H), 7.67 (dd, J = 9.0, 2.7 Hz, 1H), 7.39 (d, J = 9.0 Hz, 1H), 6.17 – 6.02 (m, 1H), 5.46 (d, J = 8.4 Hz, 1H), 4.00 (s, 3H), 3.03 (s, 3H), 2.73 (s, 3H), 2.34 (s, 3H).

LC-MS: (ES, m/z): RT = 1.526 min, LCMS 33, m/z = 383 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.62 (s, 1H), 8.29 (d, J = 2.7 Hz, 1H), 7.69 (dd, J = 9.0, 2.7 Hz, 1H), 7.37 (d, J = 9.1 Hz, 1H), 6.03 (d, J = 1.2 Hz, 1H), 3.98 (s, 3H), 3.03 (s, 3H), 2.63 (s, 3H), 2.33 (d, J = 1.0 Hz, 3H), 1.86 (s, 6H).

LC-MS: (ES, m/z): RT= 0.95 min, LCMS 33: m/z = 353 [M+1]. 1H-NMR: (Methanol- d4, ppm): δ 7.84 (d, J = 2.7 Hz, 1H), 7.63 – 7.53 (m, 2H), 7.26 (d, J = 9.0 Hz, 1H), 6.92 (s, 1H), 6.19 (d, J = 7.3 Hz, 1H), 4.38 (s, 2H), 4.02 (s, 3H), 3.05 – 2.85 (m, 9H).

LC-MS: (ES, m/z): RT= 0.95 min, LCMS 27: m/z = 354 [M+1]. 1H-NMR: (Methanol- d4, ppm): δ 8.10 (s, 1H), 7.77 – 7.58 (m, 4H), 7.34 (d, J = 9.0 Hz, 1H), 6.21 (d, J = 7.3 Hz, 1H), 4.33 (s, 2H), 3.93 (s, 3H), 2.97 (d, J = 20.4 Hz, 9H).

LC-MS: (ES, m/z): RT = 0.875 min, LCMS07, m/z = 355.10 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.75 (s, 1H), 8.32 (s, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7.39 (d, J = 9.0 Hz, 1H), 6.22 (d, J = 7.3 Hz, 1H), 4.59 (s, 2H), 3.99 (s, 3H), 3.05 (s, 3H), 2.99 (s, LC-MS: (ES, m/z): RT = 0.907 min, LCMS27: m/z = 355.0 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.40 (s, 1H), 8.33 (s, 1H), 7.74 (s, 1H), 7.65 – 7.60 (m, 1H), 7.21 (d, J = 9.1 Hz, 1H), 5.95 (d, J = 6.1 Hz, 1H), 3.98 – 3.90 (m, 5H), 2.92 (s, 3H), 2.76 (q, J = 7.2 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H).

LC-MS: (ES, m/z): RT = 1.015 min, LCMS28: m/z = 381.2 [M+1]. 1H NMR (400 MHz, ol-d4) δ 8.66 (s, 1H), 8.28 (s, 1H), 7.68 – 7.60 (m, 2H), 7.40 (d, J = 9.1 Hz, 1H), 6.23 (d, J = 7.3 Hz, 1H), 4.49 (s, 2H), 4.00 (s, 3H), 3.11 – 3.02 (m, 5H), 1.24 – 1.12 (m, 1H), 0.82 – 0.72 (m, 2H), 0.51 – 0.42 (m, 2H).

LC-MS: (ES, m/z): RT = 0.953 min, LCMS28: m/z = 348.1 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 9.11 (d, J = 1.2 Hz, 1H), 8.30 (d, J = 1.1 Hz, 1H), 8.03 (s, 1H), 7.90 (t, J = 1.2 Hz, 1H), 7.71 (d, J = 6.2 Hz, 1H), 7.70 – 7.65 (m, 1H), 7.09 (d, J = 8.9 Hz, 1H), 5.90 (d, J = 6.0 Hz, 1H), 3.85 (s, 3H), 2.89 (s, 3H).

LC-MS: (ES, m/z): RT = 1.621 min, : m/z = 347.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 9.14 (d, J = 0.7 Hz, 1H), 8.11 – 8.02 (m, 1H), 7.93 – 7.73 (m, 3H), 7.63 (d, J = 7.3 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 7.11 – 7.09 (m, 1H), 6.20 (d, J = 7.3 Hz, 1H), 3.96 (s, 3H), 3.00 (s, 3H).

LC-MS: (ES, m/z): RT = 2.222 min, LCMS15: m/z = 338.2 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.21 (s, 1H), 8.16 (s, 1H), 7.65 – 7.53 (m, 2H), 7.34 (d, J = 9.0 Hz, 1H), 6.20 (d, J = 7.3 Hz, 1H), 3.97 (s, 3H), 3.04 (s, 3H), 2.08 – 2.01 (m, 1H), 1.09 – 0.98 (m, 2H), 0.93 – 0.84 (m, 2H).

LC-MS: (ES, m/z): RT = 1.828 min; LCMS28: m/z = 354 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.46 – 8.36 (m, 1H), 8.26 (s, 1H), 7.71 – 7.56 (m, 2H), 7.40 – 7.27 (m, 1H), 6.20 (dd, J = 7.3, 1.9 Hz, 1H), 5.10 (dd, J = 8.5, 5.9 Hz, 2H), 4.99 – 4.90 (m, 2H), Attorney Docket No.: 73/001WO (311622-2509) 4.55 (tt, J = 8.5, 7.0 Hz, 1H), 4.03 – 3.91 (m, 3H), 3.08 (s, 3H).

LC-MS: (ES, m/z): RT = 1.214 min, LCMS27: m/z = 346.0 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 7.71 (s, 2H), 7.61 – 7.46 (m, 3H), 7.28 – 7.18 (m, 2H), 7.03 (d, J = 8.9 Hz, 1H), 6.51 – 6.41 (m, 1H), 5.91 (d, J = 6.0 Hz, 1H), 3.78 (s, 3H), 2.92 (s, 3H).

LC-MS: (ES, m/z): RT = 0.790 min; LCMS33: m/z = 301 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.32 (d, J = 0.7 Hz, 1H), 7.86 (d, J = 0.7 Hz, 1H), 7.67 (s, 1H), 7.42 (s, 1H), 4.24 (s, 2H), 4.01 (s, 3H), 3.73 (s, 3H), 3.18 (s, 3H), 2.77 (s, 3H).

LC-MS: (ES, m/z): RT = 1.839 min; : m/z = 340 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.46 (s, 1H), 8.09 (s, 1H), 7.87 (d, J = 2.1Hz, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.51–7.48 (m, 1H), 7.34 (d, J = 2.7 Hz, 1H), 6.21 (d, J = 2.4 Hz, 1H), 4.23 (s, 2H), 3.99 (s, 3H), 3.04 (s, 3H), 2.76 (s, 3H).

LC-MS: (ES, m/z): RT = 1.47 min, LCMS 31: m/z = 356 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.72 (d, J = 2.4 Hz, 1H), 8.60 (s, 1H), 8.38 (d, J = 2.4 Hz, 1H), 7.86 (s, 1H), 6.08 – 6.01 (m, 1H), 4.23 (s, 2H), 4.12 (s, 3H), 3.02 (s, 3H), 2.76 (s, 3H), 2.34 (s, LC-MS: (ES, m/z): RT = 1.503 min, LCMS 33, m/z =382.3 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.68 (s, 1H), 8.44 (s, 1H), 7.94 (s, 1H), 7.72 (s, 1H), 6.98 (s, 1H), 4.25 (s, 2H), 4.19 – 4.10 (m, 5H), 3.86 – 3.75 (m, 2H), 3.68 (t, J = 11.8 Hz, 1H), 3.20 (s, 3H), 2.77 (s, 3H), 2.08 – 1.81 (m, 5H).

LC-MS: (ES, m/z): RT = 1.019 min, LCMS07: m/z = 354 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.47 (d, J = 2.1 Hz, 1H), 8.08 (s, 1H), 7.90 (d, J = 1.8 Hz, 1H), 7.62 (d, J = 3.0 Hz, 1H), 7.52–7.48 (m, 1H), 7.34–7.31 (m, 1H), 6.21 (d, J = 2.7Hz, 1H), 4.23 (s, 2H), 3.99 (d, J = 1.5 Hz, 3H), 3.22 – 2.18 (m, 5H), 1.37-1.34 (m, 3H).

LC-MS: (ES, m/z): RT = 0.871 min, LCMS33: m/z = 312.2 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.04 (d, J = 0.8 Hz, 1H), 7.70 (d, J = 0.8 Hz, 1H), 7.47 (s, 1H), 7.14 (s, 1H), 3.90 (s, 3H), 3.85 (s, 2H), 2.76 – 2.65 (m, 2H), 2.62 – 2.40 (m, 6H), 2.36 – 2.28 (m, 1H).

LC-MS: (ES, m/z): RT = 1.320 min; LCMS53: m/z = 326 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.40 (s, 1H), 7.84 (s, 1H), 7.71 (s, 1H), 7.50 (s, 1H), 4.21 (s, 2H), 4.03 (s, 3H), 3.22 (s, 3H), 2.84 - 2.78 (m, 5H), 2.74 - 2.62 (m, 3H), 2.37 - 2.32 (m, 1H).

LC-MS: (ES, m/z): RT = 0.981 min, LCMS15: m/z = 381.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.66 (s, 1H), 8.58 (s, 1H), 8.36 (s, 1H), 7.89 (s, 1H), 6.05 (s, 1H), 4.74 (t, J = 7.5 Hz, 1H), 4.11 (s, 3H), 3.50 – 3.39 (m, 2H), 3.00 (s, 3H), 2.57 – 2.38 (m, 1H), 2.36 – 2.15 (m, 6H).

LC-MS: (ES, m/z): RT=1.01min, LCMS28: m/z=381.21 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.40 (s, 1H), 8.30 (s, 1H), 7.74 (s, 1H), 7.62 (dd, J = 9.0, 2.7 Hz, 1H), 7.21 (d, J = 9.0 Hz, 1H), 5.95 (d, J = 6.1 Hz, 1H), 3.92 – 3.86 (m, 5H), 3.43 – 3.33 (m, 1H), 2.92 (s, 3H), 2.28-2.18 (m, 2H), 1.92 – 1.65 (m, 4H).

LC-MS: (ES, m/z): RT= 0.96 min, LCMS 28: m/z = 353 [M+1]. 1H-NMR: (Methanol- d4, ppm):δ 8.60 (s, 1H), 7.79 (s, 1H), 7.53 (s, 1H), 4.99 (t, J = 7.8 Hz, 1H), 4.05 (s, 3H), 3.62 – 3.41 (m, 2H), 3.25 (s, 3H), 2.95 – 2.84 (m, 2H), 2.84 – 2.62 (m, 4H), 2.67 – 2.16 (m, 4H).

LC-MS: (ES, m/z): RT= 0.86 min, LCMS 07: m/z = 339 [M+1]. 1H-NMR: (Methanol- d4, ppm):δ 8.59 (s, 1H), 7.79 (s, 1H), 7.53 (s, 1H), 4.98 (t, J = 7.9 Hz, 1H), 4.05 (s, 3H), 3.60 – 3.43 (m, 2H), 2.96 – 2.81 (m, 2H), 2.79 – 2.63 (m, 3H), 2.59 – 2.53 (m,1H), 2.49 – 2.16 (m, 4H).

Attorney Docket No.: EPIZ-073/001WO (311622-2509) LC-MS: (ES, m/z): RT= 0.94 min, LCMS 28: m/z = 339 [M+1]. 1H-NMR: (Methanol- d4, ppm): δ 8.59 (s, 1H), 7.79 (s, 1H), 7.53 (s, 1H), 4.98 (t, J = 7.9 Hz, 1H), 4.05 (s, 3H), 3.60 – 3.43 (m, 2H), 2.98 – 2.82 (m, 2H), 2.79 – 2.51 (m, 4H), 2.49 – 2.16 (m, 4H).

LC-MS: (ES, m/z): RT= 0.87 min, LCMS 07: m/z = 339 [M+1]. : (Methanol- d4, ppm): δ 8.58 (s, 1H), 7.79 (s, 1H), 7.53 (s, 1H), 4.98 (t, J = 7.9 Hz, 1H), 4.05 (s, 3H), 3.60 – 3.43 (m, 2H), 2.96 – 2.81 (m, 2H), 2.79 – 2.63 (m, 3H), 2.67 – 2.51 (m, 1H), 2.49 – 2.32 (m, 3H), 2.35 – 2.16 (m, 1H).

LC-MS: (ES, m/z): RT=0.938 min, LCMS07, 9 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.80 (s, 1H), 8.47 (s, 1H), 8.21 (d, J = 18.4 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.05 (s, 1H), 5.08 – 4.98 (m, 1H), 4.16 – 4.12 (m, 4H), 4.05 (s, 1H), 3.78 – 3.85 (m, 2H), 3.67 – 3.74 (m, 1H), 3.58 – 3.47 (m, 2H), 3.21 (d, J = 2.0 Hz, 3H), 2.69 – 2.57 (m, 1H), 2.49 – 2.23 (m, 3H), 2.05 – 1.97 (m, 2H), 1.84 – 1.93 (m, 2H).

LC-MS: (ES, m/z): RT=1.128 min, LCMS28, m/z=379 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.75 (dd, J = 2.5, 1.1 Hz, 1H), 8.30 (d, J = 2.7 Hz, 1H), 8.11 (d, J = 5.7 Hz, 1H), 7.68 (dd, J = 9.0, 2.7 Hz, 1H), 7.59 (dd, J = 5.7, 1.1 Hz, 1H), 7.16 (d, J = 9.0 Hz, 1H), 5.85 (d, J = 0.8 Hz, 1H), 4.00 (s, 3H), 2.92 (s, 3H), 2.22 (s, 3H).

LC-MS: (ES, m/z): RT=1.180 min, LCMS28: m/z=375 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.90 (t, J = 0.8 Hz, 1H), 8.20 (dd, J = 6.5, 0.8 Hz, 1H), 8.10 (dd, J = 6.5, 0.8 Hz, 1H), 7.87 (dd, J = 9.0, 2.7 Hz, 1H), 7.83 – 7.70 (m, 1H), 7.33 (d, J = 9.0 Hz, 1H), 6.02 (d, J = 1.1 Hz, 1H), 3.95 (s, 3H), 2.96 (s, 3H), 2.45 (s, 3H), 2.33 (d, J = 1.0 Hz, 3H).

LC-MS: (ES, m/z): RT=4.116min, HPLC06: m/z =362 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 9.05 (s, 1H), 8.96 (s, 1H), 8.25 (d, J = 2.6 Hz, 1H), 7.82 (dd, J = 9.0, 2.7 Hz, 1H), 7.44 – 7.28 (m, 2H), 6.03 (d, J = 1.1 Hz, 1H), 4.13 (s, 3H), 3.01 (s, 3H), 2.34 (s, 3H).

LC-MS: (ES, m/z): RT= 1.00 min, LCMS53: m/z = 319 [M+1]. 1H-NMR: (Methanol- d4, ppm):δ 8.97 (s, J = 0.9 Hz, 1H), 8.30 – 8.05 (m, 2H), 7.75 (s, 1H), 7.70 (s, 1H) 7.39 (s, 1H), 4.22 (s, 3H), 2.97 – 2.84 (m, 2H), 2.81 – 2.64 (m, 3H), 2.49 – 2.35 (m, 1H).

LC-MS: (ES, m/z): RT=0.579 min, LCMS 07, m/z = 362 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 9.02 (s, 1H), 8.64 – 8.56 (m, 2H), 8.23 (d, J = 6.5, 0.8 Hz, 1H), 8.15 – 8.08 (m, 1H), 7.52 (s, 1H), 6.07 (s, 1H), 4.25 (s, 3H), 2.98 (s, 3H), 2.36 (s, 3H).

LC-MS: (ES, m/z): RT=0.579 min, LCMS 07, m/z = 362 [M+1]. 1H NMR (400 MHz, ol-d4) δ 9.02 (s, 1H), 8.64 – 8.56 (m, 2H), 8.23 (d, J = 6.5, 0.8 Hz, 1H), 8.15 – 8.08 (m, 1H), 7.52 (s, 1H), 6.07 (s, 1H), 4.25 (s, 3H), 2.98 (s, 3H), 2.36 (s, 3H).

LC-MS: (ES, m/z): RT=0.787 min, LCMS 07: m/z=324 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.65 (s, 1H), 8.30 (s, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.51 (d, J = 0.8 Hz, 1H), 6.81 (s, 1H), 6.23 (s, 1H), 4.03 (s, 3H), 3.97 (d, 1H), 3.12 (d, J = 7.5 Hz, 2H), 2.86 (t, J = 6.3 Hz, 2H), 2.01 (d, 2H), 1.42 (t, J = 5.9 Hz, 2H).

LC-MS: (ES, m/z): RT = 1.018 min, LCMS27: m/z = 361.0 [M+1]. 1H NMR (300 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.85 (s, 1H), 8.77 (s, 1H), 8.34 – 8.30 (m, 1H), 7.87 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.48 – 7.40 (m, 1H), 7.00 (d, J = 8.9 Hz, 1H), 6.83 (s, 1H), 6.57 (s, 1H), 5.73 (s, 1H), 3.78 (s, 3H), 2.83 (d, J = 4.5 Hz, 3H), 2.09 (s, 3H).

LC-MS: (ES, m/z): RT = 0.781 min, LCMS28: m/z = 375 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ8.95 (s, 1H), 8.00 – 7.74 (m, 3H), 7.42 – 7.27 (m, 1H), 6.84 – 6.77 (m, 1H), 6.06 (d, J = 1.1 Hz, 1H), 3.97 (d, J = 3.3 Hz, 3H), 2.99 (s, 3H), 2.63 (d, J = 1.1 Hz, 3H), 2.35 (d, J = 1.0 Hz, 3H).

Attorney Docket No.: EPIZ-073/001WO (311622-2509) LC-MS: (ES, m/z): 39 min, LCMS 07: m/z=324 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.65 (s, 1H), 8.30 (s, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.51 (d, J = 0.8 Hz, 1H), 6.81 (s, 1H), 6.23 (s, 1H), 4.03 (s, 4H), 3.97 (d, 2H), 3.12 (d, J = 7.5 Hz, 2H), 2.86 (t, J = 6.3 Hz, 2H), 2.01 (d, 2H).

LC-MS: (ES, m/z): RT = 1.079 min, LCMS 28: m/z = 308 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 9.14 (s, 1H), 8.05 (s, 1H), 7.89 (d, J = 3.4 Hz, 1H), 7.65 (s, 1H), 7.44 (s, 1H), 7.15 – 7.09 (m, 1H), 4.01 (s, 3H), 3.76 (s, 3H), 3.20 (s, 3H).

LC-MS: (ES, m/z): RT = 1.000 min, LCMS28: m/z = 362 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 9.29 (s, 1H), 8.83 (s, 1H), 8.28 (s, 1H), 7.98 – 7.84 (m, 2H), 7.39 – 7.27 (m, 1H), 6.21 – 6.02 (m, 1H), 3.97 (s, 3H), 2.99 (s, 3H), 2.43 (s, 1H), 2.54 – 2.15 (m, LC-MS: (ES, m/z): RT=0.941 min, LCMS07, m/z=381 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.42 (s, 1H), 8.30 (s, 1H), 7.63 (dd, J = 9.0, 2.7 Hz, 1H), 7.20 (d, J = 9.0 Hz, 1H), 5.83 (d, J = 0.8 Hz, 1H), 4.38 (t, J = 6.9 Hz, 1H), 3.89 (s, 3H), 3.22 – 3.11 (m, 1H), 3.07 – 2.96 (m, 1H), 2.91 (s, 3H), 2.38 – 2.24 (m, 1H), 2.19 (s, 3H), 2.09 – 1.89 (m, 3H).

LC-MS: (ES, m/z): RT=0.952 min, LCMS07, m/z=381 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.41 (s, 1H), 8.29 (s, 1H), 7.63 (dd, J = 9.0, 2.7 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H), 5.83 (s, 1H), 4.37 (t, J = 6.9 Hz, 1H), 3.89 (s, 3H), 3.16 – 3.19 (m, 1H), 3.07 – 2.96 (m, 1H), 2.91 (s, 3H), 2.38 – 2.24 (m, 1H), 2.19 (s, 3H), 2.08 – 1.89 (m, 3H).

LC-MS: (ES, m/z): RT= 1.10 min, : m/z = 333 [M+1]. 1H-NMR: (Methanol- d4, ppm):δ 9.16 (s, 1H), 8.04 (s, 1H), 7.90 (d, J = 3.3 Hz, 1H), 7.75 (s, 1H), 7.40 (s, 1H), 7.13 (dd, J = 3.4, 0.8 Hz, 1H), 4.04 (s, 3H), 3.26 (s, 3H), 2.97 – 2.40 (m, 6H).

LC-MS: (ES, m/z): RT=1.107 min, LCMS28: m/z=333 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.73 (d, J = 1.0 Hz, 1H), 8.04 (d, J = 5.6 Hz, 1H), 7.57 (dd, J = 5.6, 1.1 Hz, 1H), 7.50 (s, 1H), 7.45 (s, 1H), 6.95 (d, J = 0.9 Hz, 1H), 4.08 (s, 3H), 3.06 (s, 3H), 2.71 – 2.57 (m, 2H), 2.60 – 2.44 (m, 3H), 2.30 (tq, J = 9.7, 5.6, 4.8 Hz, 1H).

LC-MS: (ES, m/z): RT=1.148 min, LCMS28: m/z=367 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.71 (d, J = 1.1 Hz, 1H), 8.16 (d, J = 5.6 Hz, 1H), 7.58 (dd, J = 5.6, 1.1 Hz, 1H), 7.46 (d, J = 8.9 Hz, 2H), 3.96 (s, 3H), 3.06 (s, 3H), 2.74 – 2.62 (m, 2H), 2.64 – 2.43 (m, 3H), 2.35 – 2.22 (m, 1H).

LC-MS: (ES, m/z): RT=2.121 min, LCMS28: m/z=351[M+1]. 1H NMR (300 MHz, Methanol-d4) δ 9.05 (d, J = 2.2 Hz, 1H), 8.26 (d, J = 6.6 Hz, 1H), 8.12 (dd, J = 6.6, 0.8 Hz, 1H), 7.80 (d, J = 1.4 Hz, 2H), 4.19 (s, 3H), 3.25 (s, 3H), 2.93 – 2.62 (m, 5H), 2.48 – 2.35 (m, 1H).

LC-MS: (ES, m/z): RT = 2.136 min, LCMS53: m/z = 376.3 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 7.70 (s, 1H), 7.55 – 7.51 (m, 1H), 7.27 – 7.24 (m, 1H), 7.16 – 7.15 (m, 1H), 7.09 – 6.98 (m, 1H), 7.01 (d, J = 8.9 Hz, 1H), 5.79 (d, J = 0.7 Hz, 1H), 3.77 (s, 3H), 3.34 – 3.16 (m, 2H), 2.88 (s, 3H), 2.17 (s, 3H).

LC-MS: (ES, m/z): RT = 0.969 min, LCMS33: m/z = 377.3 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.43 (s, 1H), 7.92 (s, 1H), 7.86 (d, J = 2.7 Hz, 1H), 7.47 (s, 1H), 7.34 (d, J = 9.1 Hz, 1H), 6.02 (s, 1H), 3.96 (s, 3H), 2.97 (s, 3H), 2.33 (s, 3H).

LC-MS: (ES, m/z): RT = 0.977 min, LCMS07: m/z = 391.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.86 (s, 1H), 8.54 (d, J = 2.7 Hz, 1H), 7.49 – 7.41 (m, 2H), 6.87 (d, J = 2.4 Hz, 1H), 6.72 (s, 1H), 5.85 (s, 1H), 3.72 (s, 3H), 3.37 (s, 3H), 2.97 (s, 3H), 2.21 (s, 3H).

Attorney Docket No.: EPIZ-073/001WO (311622-2509) LC-MS: (ES, m/z): RT = 1.022 min, LCMS33: m/z = 379.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 9.23 (s, 1H), 8.03 – 7.98 (m, 3H), 7.24 – 7.18 (m, 2H), 6.05 (s, 1H), 3.94 (s, 3H), 2.94 (s, 3H), 2.34 (s, 3H).

LC-MS: (ES, m/z): RT = 0.926min, LCMS33: m/z = 384 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.61 (d, J = 2.8 Hz, 1H), 7.79 (s, 2H), 6.92 (d, J = 3.2 Hz, 1H), 5.86 (s, 1H), 3.90 (s, 2H), 3.76 (s, 3H), 3.44 (s, 3H), 2.95 (s, 3H), 2.54 (s, 3H), 2.20 (s, 3H).

LC-MS: (ES, m/z): RT =1.757 min, LCMS53: m/z = 361 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.49 (d, J = 1.9 Hz, 1H), 8.05 – 7.98 (m, 1H), 7.86 (s, 1H), 7.65 – 7.53 (m, 2H), 7.09 (d, J = 8.9 Hz, 1H), 6.69 – 6.60 (m, 1H), 5.83 (s, 1H), 3.83 (s, 3H), 2.92 (s, 3H), 2.21 (s, 3H).

LC-MS: (ES, m/z): RT = 1.022 min, LCMS33: m/z = 352.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.43 (d, J = 1.2 Hz, 1H), 8.10 – 8.02 (m, 1H), 7.69 – 7.66 (m, 1H), 7.05 (d, J = 9.0 Hz, 1H), 6.95 (d, J = 1.2 Hz, 1H), 5.79 (d, J = 0.7 Hz, 1H), 3.85 (s, 3H), 2.94 (s, 3H), 2.89 (s, 3H), 2.17 (s, 3H).

LC-MS: (ES, m/z): 75 min, LCMS07: m/z=326 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.65 (s, 1H), 8.30 (s, 1H), 8.02 (s, 1H), 6.81 (s, 1H), 4.03 (s, 4H), 3.97 (d, 2H), 3.12 (d, J = 7.5 Hz, 2H), 2.86 (t, J = 6.3 Hz, 3H), 2.01 (d, 2H), 1.86 (t, J = 5.9 Hz, 2H), 1.42 (t, J = 6.3 Hz, 2H).

LC-MS: (ES, m/z): RT=0.668 min, LCMS30: m/z=375 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 7.66 (dd, J = 8.9, 2.8 Hz, 1H), 7.60 (d, J = 1.0 Hz, 1H), 7.56 (d, J = 2.7 Hz, 1H), 7.53 (d, J = 3.3 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H), 6.57 (dd, J = 3.2, 1.0 Hz, 1H), 5.83 – 5.75 (m, 1H), 3.75 (s, 3H), 2.85 (s, 3H), 2.42 (s, 3H), 2.18 (s, 3H).

LC-MS: (ES, m/z): RT = 1.203 min, LCMS28: m/z = 379 [M+1]. 1H NMR (400 MHz, ol-d4) δ 9.24 (s, 1H), 8.02 (d, J = 2.3 Hz, 1H), 7.96 – 7.84 (m, 2H), 7.78 (d, J = 2.9 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 6.03 (d, J = 1.1 Hz, 1H), 3.96 (s, 2H), 2.99 (s, 2H), 2.36 – 2.31 (m, 2H).

LC-MS: (ES, m/z): RT=1.055 min, LCMS33, m/z=366 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.05 (s, 1H), 7.67 (dd, J = 8.9, 2.8 Hz, 1H), 7.05 (d, J = 8.9 Hz, 1H), 6.69 (s, 1H), 5.80 (d, J = 0.7 Hz, 1H), 3.84 (s, 3H), 2.93 (d, J = 16.2 Hz, 6H), 2.48 (s, 3H), 2.18 (s, 3H).

LC-MS: (ES, m/z): RT = 0.926 min, : m/z = 323 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.96 (s, 1H), 7.93 (s, 1H), 7.78 (s, 1H), 7.45 (d, J = 2.7 Hz,1H), 7.01 (d, J = 3.3 Hz, 1H), 6.54 – 6.46 (m, 2H), 3.94 (m, 3H), 3.84 – 3.74 (m, 1H), 3.55 – 3.45 (m, 2H), 3.27 – 3.17 (m, 2H), 2.35 – 2.24 (m, 2H), 1.85 – 1.69 (m, 2H).

LC-MS: (ES, m/z): RT = 1.356 min, LCMS15: m/z = 363 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.92 (d, J = 4.0 Hz, 1H), 8.28 (s, 1H), 7.86 (s, 1H), 7.76 – 7.71 (m, 1H), 7.11 (d, J = 8.0 Hz, 1H), 5.82 (s, 1H), 3.91 (s, 3H), 2.92 (s, 3H), 2.19 – 2.05 (m, 4H), 1.20 – 1.13 (m, 4H).

LC-MS: (ES, m/z): RT = 1.215 min, LCMS15 m/z = 363 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 9.01 (s, 1H), 8.01 (s, 1H), 7.95 – 7.87 (m, 1H), 7.81 – 7.62 (m, 1H), 7.33 – 7.21 (m, 1H), 6.23 – 5.97 (m, 1H), 3.97 – 3.90 (d, J = 6.0 Hz, 3H), 3.02 – 2.96 (m, 3H), 2.45 – 2.29 (m, 3H), 2.20 – 2.11 (m, 1H), 1.41 – 1.30 (m, 2H), 1.14 – 1.04 (m, LC-MS: (ES, m/z): RT = 0.98 min, LCMS27: m/z = 361.9 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 9.14 – 9.02 (m, 2H), 8.44 (s, 1H), 8.10 (t, J = 1.2 Hz, 1H), 7.83 (d, J = 1.2 Hz, 1H), 7.66 (q, J = 2.7 Hz, 1H), 7.10 (d, J = 9.3 Hz, 1H), 5.82 (d, J = 0.9 Hz, 1H), 3.94 (s, 3H), 2.95 (s, 3H), 2.19 (s, 3H).

Attorney Docket No.: EPIZ-073/001WO (311622-2509) LC-MS: (ES, m/z): RT = 2.256 min, LCMS15: m/z = 363 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ 12.79 – 11.73(m, 2H), 10.27 (s, 1H), 8.77 (s, 1H), 8.49 (s, 1H), 8.25 (s, 1H), 8.13 (s, 1H), 7.54 (d, J = 4.0 Hz, 1H), 7.19 (d, J = 4.0 Hz, 1H), 6.01 (s, 1H), 3.88 (s, 3H), 2.93 (d, J = 4.0 Hz, 3H), 2.26 (s, 3H).

LC-MS: (ES, m/z): RT = 0.942 min, : m/z = 325 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.73 (s, 1H), 7.67 (s, 1H), 7.57 – 7.51(m, 1H), 6.44 – 6.37(m, 2H), 3.84 (s, 3H), 3.63 – 3.51(m, 1H), 3.27 – 3.15 (m, 2H), 2.88 – 2.82 (m, 2H), 2.19 – 2.07 (m, 2H), 2.05 – 1.95(m, 1H), 1.59 – 1.44 (m, 2H), 1.28 – 1.16 (m, 2H), 0.99 – 0.86 (m, 2H).

LC-MS: (ES, m/z): RT=1.313 min, LCMS28, m/z=347 [M+1]. 1H NMR (400 MHz, ol-d4) δ 8.93 (d, J = 0.9 Hz, 1H), 8.21 (dd, J = 6.5, 0.8 Hz, 1H), 8.09 (dd, J = 6.6, 0.8 Hz, 1H), 7.73 (s, 1H), 7.34 (s, 1H), 4.03 (s, 3H), 3.25 (s, 3H), 2.94 – 2.80 (m, 2H), 2.78 – 2.63 (m, 3H), 2.43 (s, 4H). 241 LC-MS: (ES, m/z): RT = 3.62 min, HPLC05: m/z = 345 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 9.01 (q, J = 0.9 Hz, 1H), 8.25 (q, J = 6.6 Hz, 1H), 8.14 (d, J = 6.3 Hz, 1H), 7.94 – 7.80 (m, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.19 – 7.10 (m, 1H), 6.07 – 6.00 (m, 1H), 2.99 (s, 3H), 2.52 (s, 3H), 2.34 (s, 3H). 242 LC-MS: (ES, m/z): RT = 0.971 min, LCMS15: m/z = 335 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.91 (d, J = 2.2Hz, 1H), 8.49 (s, 1H), 8.26 – 8.35(m, 2H), 7.82 – 7.87 (m, 1H), 7.55 – 7.39 (m, 3H), 5.88 (s, 1H), 2.95 (s, 3H), 2.22 (s, 3H). 243 LC MS: (ES, m/z): RT=0.810 min, LCMS28: m/z=307 [M+1]. 1H NMR (400 MHz, ol-d4) δ 9.02 (s, 1H), 8.30 (m, 2H), 8.16 – 8.06 (m, 1H), 7.12 (d, J = 15.9 Hz, 1H), 6.97 (s, 1H), 4.12 (s, 1H), 3.54 (d, J = 12.1 Hz, 2H), 3.21 (s, J = 12.5 Hz, 2H), 2.53 (d, J = 12.3 Hz, 3H), 2.36 – 2.27 (m, 2H), 1.85 (s, 2H). 244 LC-MS: (ES, m/z): RT = 1.08 min, LCMS 33: m/z = 363 [M+1]. 1H NMR (400 MHz, Chloroform-d) δ 8.85 (s, 1H), 8.83 – 8.24 (m, 2H), 8.09 (s, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 6.3 Hz, 1H), 5.84 (s, 1H), 2.89 (s, 3H), 2.83 (q, J = 9.0 Hz, 2H), 2.20 (s, 3H), 1.24 (t, J = 0.9 Hz, 3H). 245 LC-MS: (ES, m/z): 22 min, LCMS28: m/z=370 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.42 – 9.35 (m, 2H), 9.10 (dd, J = 5.9, 1.0 Hz, 1H), 8.33 (s, 1H), 8.06 (dd, J = 5.9, 2.7 Hz, 1H), 7.93 – 7.85 (m, 1H), 7.42 (d, J = 8.9 Hz, 1H), 7.06 (s, 1H), 5.84 (s, 1H), 2.78 (d, J = 4.7 Hz, 3H), 2.14 (s, 3H). 246 LC-MS: (ES, m/z): RT=1.341 min, LCMS28: m/z=375 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 9.33 (s, 1H), 8.15 (s, 1H), 7.97 (dd, J = 8.9, 2.6 Hz, 1H), 7.54 (d, J = 3.5 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 3.5 Hz, 1H), 7.05 (s, 1H), .84 (s, 1H), 2.79 (d, J = 4.6 Hz, 3H), 2.14 (s, 3H). 247 LC-MS: (ES, m/z): RT=0.760 min, LCMS07: m/z=308 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.65 (s, 1H), 8.30 (s, 1H), 8.02 (d, J = 9.1 Hz, 2H), 7.51 (d, J = 0.8 Hz, 1H), 6.81 (s, 1H), 4.23 (s, 1H), 4.03 (s, 2H), 3.97 (d, 2H), 3.12 (d, J = 7.5 Hz, 5H), 2.86 (t, J = 6.3 Hz, 2H), 2.01 (d, 1H). 248 LC-MS: (ES, m/z): RT = 1.183 min, LCMS33: m/z = 370 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 9.00 (dd, J = 4.8, 1.4 Hz, 1H), 8.66 – 8.58 (m, 1H), 8.16 (d, J = 2.6 Hz, 1H), 7.79 (dd, J = 9.1, 4.8 Hz, 1H), 7.71 (dd, J = 8.8, 2.7 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 6.07 (d, J = 1.1 Hz, 1H), 3.02 (s, 3H), 2.35 (d, J = 1.0 Hz, 3H). 249 LC-MS: (ES, m/z): RT = 1.181 min, LCMS28: m/z = 359 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.25 (s, 1H), 7.79 – 7.68 (m, 2H), 7.38 (d, J = 8.8 Hz, 1H), 7.15 (s, 1H), .88 (s, 1H), 2.92 (s, 3H), 2.21 (s, 3H).

Attorney Docket No.: EPIZ-073/001WO (311622-2509) 250 LC-MS: (ES, m/z): RT =1.274 min, LCMS27: m/z = 368 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.23 (s, 1H), 7.78 – 7.64 (m, 3H), 7.45 – 7.32 (m, 3H), 7.24 – 7.11 (m, 1H), 5.87 (d, J = 0.7 Hz, 1H), 2.91 (s, 3H), 2.21 (s, 3H). 251 LC-MS: (ES, m/z): RT = 1.04 min, LCMS27: m/z = 369.9 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 9.52 (d, J = 1.5 Hz, 1H), 8.47 – 8.35 (m, 2H), 8.29 – 8.22 (m, 1H), 7.77 (q, J = 2.7 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 5.88 (s, 1H), 2.90 (s, 3H), 2.21 (s, 3H). 252 LC-MS: (ES, m/z): RT= 1.36 min, : m/z = 375 [M+1]. 1H-NMR: (Methanold4 , ppm): 8.86 (d, J = 2.3 Hz, 1H), 8.06 (d, J = 2.6 Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.69 (dd, J = 8.8, 2.7 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 6.07 (d, J = 1.1 Hz, 1H), 3.01 (s, 3H), 2.34 (s, 3H). 253 LC-MS: (ES, m/z): RT=2.424 min, LCMS07: m/z=358.7 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.26 (d, J = 1.1 Hz, 1H), 8.05 (dd, J = 13.5, 1.9 Hz, 2H), 7.69 (dd, J = 8.8, 2.7 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 6.07 (s, 1H), 3.01 (s, 3H), 2.34 (s, 3H). 254 LC-MS: (ES, m/z): RT= 1.10 min, LCMS28: m/z = 371 [M+1]. 1H-NMR: nold4 , ppm): 8.68 (d, J = 1.7 Hz, 1H), 8.07 (d, J = 2.7 Hz, 1H), 7.98 – 7.85 (m, 1H), 7.60 – 7.49 (m, 2H), 6.06 (d, J = 1.0 Hz, 1H), 3.96 (s, 3H), 3.01 (s, 3H), 2.35 (s, 3H). 255 LC-MS: (ES, m/z): RT=2.004 min, LCMS28: m/z=365 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 9.24 (d, J = 3.8 Hz, 1H), 8.13 – 8.05 (m, 2H), 8.01 (d, J = 2.7 Hz, 1H), 7.94 (d, J = 3.3 Hz, 1H), 7.76 – 7.64 (m, 1H), 7.17 (dd, J = 3.4, 0.9 Hz, 1H), 6.07 (d, J = 1.1 Hz, 1H), 2.99 (d, J = 7.7 Hz, 3H), 2.38 – 2.33 (m, 3H). 256 LC-MS: (ES, m/z): RT=1.716 min, LCMS53: m/z=345 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 9.19 (d, J = 0.9 Hz, 1H), 7.96 (t, J = 0.8 Hz, 1H), 7.93 – 7.87 (m, 2H), 7.85 – 7.78 (m, 1H), 7.49 (dd, J = 15.3, 8.4 Hz, 1H), 7.15 (dd, J = 3.4, 0.9 Hz, 1H), 6.23 – 6.03 (m, 1H), 2.97 (d, J = 3.5 Hz, 3H), 2.46 – 2.26 (m, 6H). 257 LC-MS: (ES, m/z): RT=1.342 min, LCMS53: m/z=292 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 9.20 (d, J = 0.9 Hz, 1H), 7.96 (d, J = 0.9 Hz, 1H), 7.93 (d, J = 3.4 Hz, 1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.16 (dd, J = 3.4, 0.9 Hz, 1H), 3.73 (s, 3H), 3.20 (s, 3H), 2.42 (d, J = 0.6 Hz, 3H). 258 LC-MS: (ES, m/z): RT = 0.91 min, LCMS 27: m/z = 370 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.68 (d, J = 4.8 Hz, 2H), 8.25 (s, 1H), 7.74 (q, J = 2.7 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 7.23 (t, J = 4.9 Hz, 1H), 5.87 (d, J = 0.9 Hz, 1H), 2.90 (s, 3H), 2.21 (s, 259 LC-MS: (ES, m/z): RT = 1.02 min, LCMS 53: m/z = 369.9 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.92 – 8.85 (m, 1H), 8.70 (q, J = 5.7 Hz, 1H), 8.33 (q, J = 5.7 Hz, 1H), 8.25 (s, 1H), 7.77 (q, J = 2.7 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 5.88 (d, J = 0.9 Hz, 1H), 2.90 (s, 3H), 2.21 (s, 3H). 260 LC-MS: (ES, m/z): RT = 1.797 min, LCMS31: m/z = 381.2 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.33 (d, J = 0.9 Hz, 1H), 8.04 (d, J = 4.3 Hz, 1H), 7.77 – 7.73 (m, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.14 (s, 1H), 5.84 (s, 1H), 3.36 (s, 2H), 2.86 (s, 3H), 2.18 (s, 3H). 261 LC-MS: (ES, m/z): RT = 0.969 min, LCMS33: m/z = 377.3 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.43 (s, 1H), 7.92 (s, 1H), 7.86 (d, J = 2.7 Hz, 1H), 7.47 (s, 1H), 7.34 (d, J = 9.1 Hz, 1H), 6.02 (s, 1H), 3.96 (s, 3H), 2.97 (s, 3H), 2.33 (s, 3H). 262 LC-MS: (ES, m/z): RT = 1.03 min, LCMS 27: m/z = 358 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.32 – 8.15 (m, 2H), 7.95 – 7.86 (m, 1H), 7.77 (q, J = 8.7 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 6.07 (d, J = 1.2 Hz, 1H), 4.24 (s, 2H), 3.02 (s, 3H), 2.76 (s, 3H), 2.35 (d, J = 0.9 Hz, 3H).

Attorney Docket No.: EPIZ-073/001WO (311622-2509) 263 LC-MS: (ES, m/z): RT= 1.04 min, LCMS28: m/z = 224 [M+1]. 1H-NMR: (Methanold4 , ppm):δ 9.07 – 9.00 (m, 1H), 8.26 (dd, J = 6.5, 0.8 Hz, 1H), 8.14 (dd, J = 6.4, 0.8 Hz, 1H), 7.52 – 7.37 (m, 2H), 7.28 (dd, J = 8.2, 2.4 Hz, 1H), 7.11 (d, J = 0.8 Hz, 1H), 2.49 (s, 3H). 264 LC-MS: (ES, m/z): RT=0.970 min, LCMS 27: m/z =225.0 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.95 (s, 1H), 8.22 (d, J = 6.5 Hz, 1H), 8.10 (d, J = 6.5 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 7.08 – 7.02 (m, 2H), 6.91 (dd, J = 8.3, 2.7 Hz, 1H), 2.41 (s, 3H). 266 LC-MS: (ES, m/z): RT=1.137 min, LCMS 07: m/z= 280 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.82 (s, 1H), 7.45 (d, J = 9.0, 2.8 Hz, 2H), 6.91 (d, J = 9.1 Hz, 2H), 6.73 (d, J = 0.8 Hz, 1H), 4.61 (s, 2H), 2.21 (s, 3H). 267 LC-MS: (ES, m/z): 4min, LCMS33: m/z=210.15 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.75 (s, 1H), 8.68 (s, 1H), 8.47 (d, J = 5.1 Hz, 1H), 8.13 (d, J = 5.6 Hz, 1H), 7.67 (dd, J = 5.6, 1.1 Hz, 1H), 7.47 (d, J = 5.3 Hz, 1H), 6.79 (d, J = 0.8 Hz, 1H), 2.70 – 2.42 (m, 3H). 268 LC-MS: (ES, m/z): RT=0.659 min, LCMS 07, m/z=210 [M+H]. 1H NMR (400 MHz, Methanol-d4) δ 8.95 (s, 1H), 8.30 (s, 1H), 8.02 (s, 1H), 7.65 (s, 1H), 7.58 (s, 1H), 7.40 (d, 1H), 6.72 (s, 1H), 2.35 (s, 3H). 271 LC-MS: (ES, m/z): RT = 1.849 min, : m/z =370 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 9.26 (s, 1H), 8.53 (d, J = 6.4 Hz, 1H), 8.32 (d, J = 6.4 Hz, 1H), 7.93 – 7.90 (m, 2H), 7.57 (d, J = 8.1 Hz, 1H), 6.04 (s, 1H), 2.99 (s, 3H), 2.47 – 2.34 (m, 6H). 273 LC-MS: (ES, m/z): RT = 1.428 min, LCMS53: m/z = 231 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.87 (s, 1H), 8.17 (d, J = 6.5 Hz, 1H), 8.05 (d, J = 6.5 Hz, 1H), 7.13 (s, 1H), 2.61 (s, 3H). 274 LC-MS: (ES, m/z): RT = 1.806 min, LCMS53: m/z = 344 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 7.91 (s, 1H), 7.62 – 7.50 (m, 2H), 7.44 – 7.34 (m, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.16 – 7.04 (m, 1H), 7.07 – 6.95 (m, 1H), 6.52 (d, J = 0.9 Hz, 1H), 5.81 (d, J = 0.7 Hz, 1H), 2.89 (s, 3H), 2.44 (s, 3H), 2.19 (s, 3H). 275 LC-MS: (ES, m/z): RT = 1.062 min, LCMS28: m/z = 231 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.91 – 8.84 (m, 1H), 8.26 – 8.15 (m, 1H), 8.08 – 8.97 (m, 1H), 7.06 (d, J = 0.8 Hz, 1H), 2.55 (s, 3H). 276 LC-MS: (ES, m/z): RT = 0.975 min, LCMS33: m/z = 365.3 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 7.52 – 7.40 (m, 2H), 7.36 – 7.20 (m, 3H), 5.98 (s, 1H), 3.21 – 3.18 (m, 2H), 2.97 (s, 3H), 2.31 – 2.19 (m, 6H), 1.34 – 1.29 (m, 3H). 278 LC-MS: (ES, m/z): RT=1.130 min, LCMS28: m/z=292 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 9.04 – 8.98 (m, 1H), 8.26 (d, J = 6.4 Hz, 1H), 8.15 (d, J = 6.5 Hz, 1H), 7.63 (s, 1H), 7.58 (s, 1H), 7.13 (d, J = 0.7 Hz, 1H), 3.72 (s, 3H), 3.20 (s, 3H), 2.62 (s, 279 LC-MS: (ES, m/z): 48 min, LCMS 27: m/z =346.0 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.93 (d, J = 1.0 Hz, 1H), 8.36 (d, J = 5.7 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 7.77 – 7.71 (m, 1H), 7.67 (dd, J = 5.6, 1.1 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), .83 (s, 1H), 2.87 (s, 3H), 2.48 (s, 3H), 2.19 (s, 3H). 280 LC-MS: (ES, m/z): min, LCMS33: m/z=355.15 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.85 (d, J = 2.2 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.58 (dd, J = 8.3, 2.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 6.03 (d, J = 1.1 Hz, 1H), 3.002-2.98(m, 3H), 2.5-2.42 (m, 3H), 2.33 (s, 3H). 282 LC-MS: (ES, m/z): RT=2.054 min, LCMS28: m/z=346 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 9.28 (d, J = 1.3 Hz, 1H), 8.84 (d, J = 1.0 Hz, 1H), 8.32 – 8.21 (m, 2H), Attorney Docket No.: EPIZ-073/001WO (311622-2509) 7.74 – 7.62 (m, 2H), 7.35 (d, J = 8.5 Hz, 1H), 5.85 (d, J = 0.7 Hz, 1H), 2.84 (s, 3H), 2.18 (d, J = 7.7 Hz, 6H). 284 LC-MS: (ES, m/z): RT=1.313 min, LCMS28: 7 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.93 (d, J = 0.9 Hz, 1H), 8.21 (dd, J = 6.5, 0.8 Hz, 1H), 8.09 (dd, J = 6.6, 0.8 Hz, 1H), 7.73 (s, 1H), 7.34 (s, 1H), 4.03 (s, 3H), 3.25 (s, 3H), 2.94 – 2.80 (m, 2H), 2.78 – 2.63 (m, 3H), 2.43 (s, 4H). 285 LC-MS: (ES, m/z): RT = 0.942 min; LCMS53: m/z = 354 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.40 (s, 1H), 8.25 – 8.15 (m, 1H), 7.81 (d, J = 0.7 Hz, 1H), 7.55 (d, J = 9.0 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 6.00 (d, J = 1.2 Hz, 1H), 4.21 (d, J = 2.1 Hz, 2H), 3.95 (s, 3H), 3.00 (s, 3H), 2.74 (s, 3H), 2.31 (s, 3H). 286 LC-MS: (ES, m/z): RT=1.290 min, LCMS 28: m/z =338.1 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.10 – 8.07 (m, 1H), 7.90 – 7.86 (m, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.75 – 7.62 (m, 1H), 7.47 – 7.39 (m, 1H), 6.25 – 6.02 (m, 1H), 4.24 (s, 2H), 2.98 (d, J = 1.4 Hz, 3H), 2.77 (d, J = 2.4 Hz, 3H), 2.44 – 2.30 (m, 3H), 2.23 (d, J = 6.9 Hz, 3H). 287 LC-MS: (ES, m/z): RT=2.288 min, LCMS 07: m/z=350 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 9.53 (s, 1H), 7.58 (s, 1H), 8.47 (s, 1H), 8.35 (s, 1H), 8.13 (d, J = 10.1 Hz, 1H), 7.61 (d, J = 9.1 Hz, 1H), 7.22 (d, J = 3.7 Hz, 1H), 5.81 (s, 1H), 2.93 (s, 3H), 2.41 (s, 3H), 2.17 (s, 3H). 288 LC-MS: (ES, m/z): RT=1.107 min, LCMS28: m/z=333 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.73 (d, J = 1.0 Hz, 1H), 8.04 (d, J = 5.6 Hz, 1H), 7.57 (dd, J = 5.6, 1.1 Hz, 1H), 7.50 (s, 1H), 7.45 (s, 1H), 6.95 (d, J = 0.9 Hz, 1H), 4.08 (s, 3H), 3.06 (s, 3H), 2.71 – 2.57 (m, 2H), 2.60 – 2.44 (m, 3H), 2.30 (tq, J = 9.7, 5.6, 4.8 Hz, 1H). 289 LC-MS: (ES, m/z): RT=1.313 min, LCMS28, m/z=347 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.93 (d, J = 0.9 Hz, 1H), 8.21 (dd, J = 6.5, 0.8 Hz, 1H), 8.09 (dd, J = 6.6, 0.8 Hz, 1H), 7.73 (s, 1H), 7.34 (s, 1H), 4.03 (s, 3H), 3.25 (s, 3H), 2.94 – 2.80 (m, 2H), 2.78 – 2.63 (m, 3H), 2.43 (s, 4H). 292 LC-MS: (ES, m/z): RT= 1.39 min, : m/z = 386 [M+1]. 1H-NMR: (Methanold4 , ppm): δ 8.33 – 8.24 (m, 2H), 7.68 (d, J = 3.3 Hz, 1H), 7.48 (dd, J = 8.8, 2.8 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 6.82 – 6.74 (m, 1H), 6.01 (d, J = 1.1 Hz, 1H), 3.96 (s, 3H), 3.11 (s, 3H), 2.32 (d, J = 1.0 Hz, 3H). 293 LC-MS: (ES, m/z): RT= 1.01 min, LCMS33: m/z = 432 [M+1]. 1H-NMR: (Methanold4 , ppm): δ 8.03 – 7.75 (m, 4H), 7.32 (dd, J = 12.6, 8.9 Hz, 1H), 7.19 (dd, J = 3.4, 0.9 Hz, 1H), 6.02 (s, 1H), 5.00 (s, 2H), 3.97 (d, J = 4.7 Hz, 3H), 2.98 (s, 3H), 2.34 (d, J = 0.9 Hz, 3H), 2.07 (s, 3H). 294 LC-MS: (ES, m/z): RT=0.98min, LCMS33:m/z=333.17 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J = 1.5 Hz, 1H), 8.69 (t, J = 1.2 Hz, 1H), 8.20 (d, J = 3.3 Hz, 1H), 7.70 (s, 1H), 7.30 (s, 1H), 6.94 (dd, J = 3.3, 1.0 Hz, 1H), 4.00 (s, 3H), 3.25 (s, 3H), 2.9-2.82 (m, 2H), .62 (m, 3H), 2.48 – 2.34 (m, 1H). 295 LC-MS: (ES, m/z): RT=0.90min, LCMS33: 8.16 [M +1]. 1H NMR (400 MHz, Methanol-d4) δ 8.73 (d, J = 1.5 Hz, 1H), 8.66 (s, 1H), 8.16 (d, J = 3.3 Hz, 1H), 7.54 (s, 1H), 7.38 (s, 1H), 6.92 (dd, J = 3.3, 0.9 Hz, 1H), 3.98 (s, 3H), 3.74 (s, 3H), 3.19 (s, 3H). 296 LC-MS: (ES, m/z): RT= 1.30 min, LCMS07: m/z = 390 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.11 (d, J = 1.0 Hz, 1H), 8.02 – 7.86 (m, 2H), 7.74 (d, J = 3.4 Hz, 1H), 7.32 – 7.18 (m, 1H), 7.01 (dd, J = 3.4, 1.0 Hz, 1H), 6.00 (d, J = 1.0 Hz, 1H), 4.75 (s, 2H), 3.95 (s, 3H), 2.99 (s, 3H), 2.33 (d, J = 0.9 Hz, 3H). 297 LC-MS: (ES, m/z): RT=1.163 min, LCMS28, m/z=296 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.84 (t, J = 0.8 Hz, 1H), 8.15 (dd, J = 6.5, 0.8 Hz, 1H), 8.02 (dd, J = 6.5, ey Docket No.: EPIZ-073/001WO (311622-2509) 0.7 Hz, 1H), 7.69 (d, J = 1.9 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.29 (dd, J = 8.4, 1.9 Hz, 1H), 3.92 (s, 3H), 2.41 (s, 3H), 2.20 (s, 3H). 298 LC-MS: (ES, m/z): RT=1.138 min, LCMS28, m/z=311 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.80 (d, J = 0.8 Hz, 1H), 8.14 (dd, J = 6.5, 0.8 Hz, 1H), 8.01 (dd, J = 6.5, 0.8 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.05 (dd, J = 8.4, 2.0 Hz, 1H), 3.93 (s, 3H), 2.83 (s, 3H), 2.42 (s, 3H). 299 LC-MS: (ES, m/z): RT=1.56min, LCMS33: m/z=353.18 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.26 (s, 1H), 7.94 (s, 1H), 7.57 (dd, J = 8.3, 2.4 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 6.04 (s, 1H), 4.14 (s, 3H), 3.00 (s, 3H), 2.47 (s, 3H), 2.33 (s, 3H). 300 LC-MS: (ES, m/z): 41 min, LCMS07: 7 [M+1]. 1H-NMR-PH-EPI-K- 1211-200: 1H NMR (400 MHz, Methanol-d4) δ 8.31 (s, 1H), 7.58 (s, 1H), 8.07 (s, 1H), 7.65 (s, 1H), 7.13 (s, 1H), 6.87 (d, J = 9.1 Hz, 1H), 3.91 (s, 3H), 3.21 (s, 3H), 2.87 (d, J = 9.1 Hz, 2H), 2.65 (d, J = 10.3 Hz, 3H), 2.57 (s, 3H), 2.33 (s, J = 10.3 Hz, 1H). 301 LC-MS: RT = 0.623 min, LCMS 32: m/z = 282 [M+1]. 1H NMR (400 MHz, Methanold4 ) δ 8.92 (s, 1H), 8.20 (d, J = 6.5 Hz, 1H), 8.09 (d, J = 6.5 Hz, 1H), 7.73 – 7.61 (m, 2H), 7.41 – 7.28 (m, 1H), 4.26 (s, 2H), 3.96 (s, 3H), 2.76 (s, 3H), 2.43 (s, 3H). 302 LC-MS: (ES, m/z): RT = 1.029 min, LCMS53: m/z = 352 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.97 (s, 1H), 8.00 – 7.75 (m, 2H), 7.41 – 7.32 (m, 2H), 7.07 (d, J = 8.0 Hz, 1H), 6.93 (s, 1H), 5.77 (s, 1H), 3.65 (s, 3H), 2.79 (d, J = 4.0 Hz, 3H), 2.25 (s, 3H), 2.12 (s, 3H). 306 LC-MS: (ES, m/z): RT = 0.856 min, LCMS27: m/z = 352 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.10 (s, 1H), 7.91 (s, 1H), 7.79 – 7.69 (m, 1H), 7.06 (d, J = 8.9 Hz, 1H), 6.45 (d, J = 6.2 Hz, 1H), 5.81 (s, 1H), 3.83 (s, 3H), 2.97 (s, 3H), 2.89 (s, 3H), 2.19 (s, 307 LC-MS: (ES, m/z): RT = 0.868 min, LCMS07: m/z = 360 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 8.47 – 8.43 (m, 1H), 7.88 (s, 1H), 7.80 (s, 1H), 7.14 – 7.11 (m, 1H), .88 (d, J = 1.2Hz, 1H), 3.74 (s, 2H), 2.88 (s, 3H), 2.43 (s, 3H), 2.19 (s, 3H). 308 LC-MS: (ES, m/z): RT= 1.94 min, LCMS07: m/z = 376 [M+1]. 1H-NMR: (Methanol-d4, ppm): δ 8.22 (d, J = 1.0 Hz, 1H), 7.76 (d, J = 3.3 Hz, 1H), 7.68 (d, J = 2.5 Hz, 2H), 7.30 (dd, J = 3.3, 0.8 Hz, 1H), 4.06 (s, 3H), 3.25 (s, 3H), 2.87 (s, 2H), 2.68 (d, J = 8.6 Hz, 3H), 2.41 (d, J = 13.8 Hz, 1H). 309 LC-MS: RT = 1.014 min, LCMS 07: m/z = 376 [M+1]. 1H NMR (400 MHz, Methanold4 ) δ 9.14 (s, 1H), 8.03 (s, 1H), 7.88 (d, J = 3.3 Hz, 1H), 7.75 (s, 1H), 7.39 (s, 1H), 7.11 (d, J = 3.3 Hz, 1H), 4.37 (s, 2H), 4.04 (s, 3H), 3.03 – 2.85 (m, 2H), 2.79 – 2.65 (m, 3H), 2.48 – 2.34 (m, 1H). 310 LC-MS: (ES, m/z): RT=1.063 min, LCMS28: m/z=337 [M+1]. 1H NMR (400 MHz, Methanol-d4) δ 8.73 (s, 1H), 8.08 (dd, J = 6.6, 0.8 Hz, 1H), 7.95 – 7.88 (m, 1H), 7.41 (d, J = 8.3 Hz, 1H), 6.52 – 6.44 (m, 2H), 3.91 (s, 3H), 3.85 – 3.73 (m, 1H), 3.47 – 3.52 (m, 2H), 3.18 – 3.25 (m, 2H), 2.42 (s, 3H), 2.30 (dd, J = 14.7, 3.8 Hz, 2H), 1.72 – 1.82 (m, 2H). 317 LC-MS: (ES, m/z): RT= 1.68 min, LCMS07: m/z = 372 [M+1]. 1H-NMR: (Methanold4 , ppm): δ 8.04 (s, 1H), 7.91 (s, 1H), 7.82 – 7.65 (m, 1H), 7.18 – 7.12 (m, 1H), 6.03 (s, 1H), 4.23 (s, 2H), 3.88 (s, 3H), 2.94 (s, 3H), 2.76 (s, 3H), 2.32 (s, 3H). 386 LC-MS: (ES, m/z): RT = 0.784 min, LCMS28: m/z = 375 [M+1]. 1H NMR (300 MHz, Methanol-d4) δ 9.09 (s, 1H), 8.01 – 7.98 (m, 1H), 7.94 – 7.74 (m, 2H), 7.64 (d, J = 1.3 Hz, 1H), 7.41 – 7.27 (m, 1H), 6.07 (d, J = 1.2 Hz, 1H), 3.97 (d, J = 3.3 Hz, 3H), 2.99 (s, 3H), 2.53 (d, J = 1.2 Hz, 3H), 2.39 – 2.32 (m, 3H).

Attorney Docket No.: 73/001WO (311622-2509) Example 20: Bioactivity Assays MATERIALS AND EQUIPMENT: Recombinant purified human EHMT2 913-1193 (55 µM) synthesized by Viva was used for all experiments. Biotinylated histone peptides were synthesized by Biopeptide and HPLC- purified to > 95% . Streptavidin Flashplates and seals were purchased from PerkinElmer and 384 Well V-bottom Polypropylene Plates were from Greiner. 3H-labeled S- adenosylmethionine (3H-SAM) was obtained from an Radiolabeled Chemicals with a specific activity of 80 Ci/mmol. Unlabeled SAM and S-adenosylhomocysteine (SAH) were ed from American Radiolabeled Chemicals and Aldrich respectively. Flashplates were washed in a Biotek ELx-405 with 0.1% Tween. 384-well Flashplates and 96-well filter binding plates were read on a TopCount microplate reader (PerkinElmer). nd serial dilutions were performed on a Freedom EVO (Tecan) and spotted into assay plates using a Thermo Scientific Matrix ate o Scientific). Reagent cocktails were added by Multidrop Combi (Thermo Scientific).

MDA-MB-231 cell line was purchased from ATCC (Manassas, VA, USA).

RPMI/Glutamax medium, Penicillin-Streptomycin, Heat Inactivated Fetal Bovine Serum, and DPBS were purchased from Life Technologies (Grand Island, NY, USA). Odyssey blocking buffer, 800CW goat anti-mouse IgG (H+L) antibody, and Licor Odyssey Infrared Scanner were purchased from Licor Biosciences, Lincoln, NE, USA. H3K9me2 mouse monoclonal antibody (Cat #1220) was purchased from Abcam (Cambridge, MA, USA). 16% Paraformaldehyde was purchased from on Microscopy es, Hatfield, PA, USA).MDA-MB-231 cells were maintained in complete growth medium (RPMI supplemented with 10% v/v heat inactivated fetal bovine serum) and cultured at 37 °C under 5% CO2. UNC0638 was purchased from Sigma- Aldrich (St. Louis, MO, USA).

Various In vitro or in vivo biological assays are may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity , electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

General Procedure for EHMT2 Enzyme Assay on Histone Peptide Substrate. 10- point curves of test compounds were made on a Freedom EVO ) using serial 3-fold dilutions in DMSO, beginning at 2.5 mM (final top concentration of compound was 50 μM and Attorney Docket No.: EPIZ-073/001WO (311622-2509) the DMSO was 2%). A 1 μL aliquot of the inhibitor dilution series was spotted in a polypropylene 384-well V-bottom plate (Greiner) using a Thermo Scientific Matrix PlateMate (Thermo Scientific). The 100% inhibition control consisted of 1 mM final tration of the product tor S-adenosylhomocysteine (SAH, Sigma-Aldrich). Compounds were incubated for 30 minutes with 40 μL per well of 0.031 nM EHMT2 (recombinant purified human EHMT2 913- 1193, Viva) in 1X assay buffer (20 mM Bicine [pH 7.5], 0.002% Tween 20, 0.005% Bovine Skin Gelatin and 1 mM TCEP). 10 μL per well of substrate mix comprising assay buffer, 3H-SAM (3H- labeled S-adenosylmethionine, American abeled Chemicals, specific activity of 80 Ci/mmol), unlabeled SAM (American Radiolabeled Chemicals), and peptide representing e H3 residues 1-15 containing inal biotin (appended to a inal amide-capped lysine, synthesized by Biopeptide and HPLC-purified to greater than 95% purity) were added to te the on (both substrates were present in the final reaction mixture at their respective Km values, an assay format referred to as "balanced ions"). Reactions were incubated for 60 minutes at room temperature and quenched with 10 μL per well of 400 μM unlabeled SAM, then transferred to a 384-well streptavidin Flashplate (PerkinElmer) and washed in a Biotek ELx-405 well washer with 0.1% Tween after 60 minutes. 384-well Flashplates were read on a TopCount microplate reader (PerkinElmer).

General Procedure for MDA-MB-231 HEK9me2 in-cell n Assay. Compound (100 nL) was added directly to 384-well cell plate. MDA-MB-231 cells (ATCC) were seeded in assay medium Glutamax supplemented with 10% v/v heat inactivated fetal bovine serum and 1% Penicillin/Streptomycin, Life Technologies) at a concentration of 3,000 cells per well to a Poly-D-Lysine coated 384-well cell culture plate with 50 µL per well. Plates were incubated at 37°C, 5% CO2 for 48 hours (BD Biosciences 356697). Plates were incubated at room temperature for 30 minutes and then incubated at 37°C, 5% CO2 for additional 48 hours. After the incubation, 50 µL per well of 8% paraformaldehyde (Electron copy Sciences) in PBS was added to the plates and incubated at room temperature for 20 minutes. Plates were transferred to a Biotek 406 plate washer and washed 2 times with 100 µL per well of wash buffer (1X PBS containing 0.3% Triton X-100 (v/v)). Next, 60 µL per well of Odyssey blocking buffer (Licor Biosciences) was added to each plate and incubated for 1 hour at room temperature. Blocking buffer was removed and 20 µL of monoclonal primary antibody α-H3K9me2 (Abcam) diluted 1:800 in Odyssey buffer with 0.1% Tween 20 (v/v) were added and plates were incubated ght (16 hours) at 4 °C.

Plates were washed 5 times with 100 µL per well of wash buffer. Next 20 µL per well of Attorney Docket No.: EPIZ-073/001WO (311622-2509) secondary antibody was added (1:500 800CW donkey ouse IgG (H+L) antibody (Licor Biosciences), 1:1000 DRAQ5 (Cell Signaling Technology) in Odyssey buffer with 0.1% Tween (v/v)) and incubated for 1 hour at room temperature. The plates were washed 5 times with 100 µL per well wash buffer then 2 times with 100 µL per well of water. Plates were allowed to dry at room temperature then imaged on a Licor Odyssey Infrared r (Licor Biosciences) which measured integrated intensity at 700 nm and 800 nm wavelengths. Both 700 and 800 channels were scanned.

% Inhibition Calculation. First, the ratio for each well was determined by: Each plate included fourteen l wells of DMSO only treatment (Minimum Inhibition) as well as fourteen control wells (background wells) for maximum inhibition treated with control nd UNC0638 (Background wells).

The average of the ratio values for each well was calculated and used to determine the percent inhibition for each test well in the plate. Control compound was ly diluted three-fold in DMSO for a total of 10 test concentrations beginning at 1 µM. Percent inhibition was calculated as: Percent Inhibition = 100- IC50 curves were generated using triplicate wells per concentration of compound. The IC50 is the concentration of compound at which measured methylation is inhibited by 50% as interpolated from the dose response curves. IC50 values were calculated using a non-linear regression ble four ter fit model) with by the following formula: , where Top is fixed at 100% and Bottom is fixed to 0%, [I] = concentration of inhibitor, IC50 = half maximal inhibitory concentration and n = Hill Slope.

The IC50 values are listed in Table 3 below ("A" means IC50 <100 nM; "B" means IC50 ranging n 100 nM and 1 µM; "C" means IC50 ranging between >1 µM and 10 µM; "D" means IC50 >10 µM; "-" or "ND" means not determined).

Table 3 Compound EHMT2 PEP EHMT1 PEP EHMT2 ICW No. (IC50 µM) (IC50 µM) (IC50 µM) ey Docket No.: EPIZ-073/001WO (311622-2509) Compound EHMT2 PEP EHMT1 PEP EHMT2 ICW No. (IC50 µM) (IC50 µM) (IC50 µM) 1 A A B 2 A A B 3 C B D 4 C C C C B C 6 D D D 7 C B C 8 D C D 9 D D D B B B 11 D D D 12 D D D 13 C B C 14 C B C D D D 19 C C C 21 D D D 22 D C D 23 A A C 24 C C D 26 D C D 27 B B C 28 C C C D D D 31 D D D 32 D D D 33 D D D C C C 36 D C D 37 D D D 38 D C D 39 D D D 40 B A B 41 D C D 42 D D D 43 D C D 45 D D D 47 C C D 48 B A C 49 D D D 50 B B D 54 D D D 56 D C D 57 C B C Attorney Docket No.: EPIZ-073/001WO 2-2509) Compound EHMT2 PEP EHMT1 PEP EHMT2 ICW No. (IC50 µM) (IC50 µM) (IC50 µM) 60 D C C 61 D C D 62 D C D 65 D C D 66 B A B 67 D C D 68 D D D 69 D D D 70 B B C 73 D C D 74 B A B 75 D D D 76 D D D 77 D D D 78 C C D 79 C C D 81 C C C 82 B B C 83 D D D 84 C C C 86 D D D 87 B A B 88 B B D 93 D C D 94 D C D 95 D D D 96 D D D 99 C C C 100 D D C 102 C B C 103 D D D 104 D C D 105 D D D 106 D D D 108 A A A 109 A A A 113 A A B 116 C C C 117 D D D 119 D C D 121 B B B 122 C B C 125 B A B 134 D D D Attorney Docket No.: 73/001WO (311622-2509) Compound EHMT2 PEP EHMT1 PEP EHMT2 ICW No. (IC50 µM) (IC50 µM) (IC50 µM) 136 B B B 137 A A B 138 D D D 139 D D D 143 B B C 144 C C D 145 D D D 146 D B C 148 C B C 151 B B B 155 D D D 156 D D C 157 A A B 158 B A B 159 A A B 160 A A B 161 C B C 163 C C C 164 B B B 165 D D D 166 D C D 169 C B C 170 B A B 171 A A B 172 B B C 173 C A C 174 D D C 175 A A B 176 C B C 177 D C D 178 D D D 179 B B C 181 A A B 182 B A B 184 B B C 185 B B C 186 A A B 187 A A B 188 B B C 191 C B D 192 A A B 193 A A B 194 A A B 195 B B C ey Docket No.: EPIZ-073/001WO (311622-2509) Compound EHMT2 PEP EHMT1 PEP EHMT2 ICW No. (IC50 µM) (IC50 µM) (IC50 µM) 196 B B C 199 A A C 200 A A A 201 C C D 202 A A C 203 C B C 204 C C D 205 D C D 206 A A A 207 A A B 208 C C D 209 C B D 210 C A C 212 A A B 213 B A B 214 A A B 215 A A B 216 A A B 217 A A B 218 D D C 219 C B D 220 D C D 221 B A B 222 B A B 223 A A B 225 C A C 227 C C D 228 A A B 229 B A B 230 B A C 231 C C D 232 D C C 233 C B C 234 D B C 235 D D D 236 D D D 237 A A B 238 A A A 239 D D D 240 D C D 241 A A B 242 D D D 243 C B D 244 D D D Attorney Docket No.: 73/001WO (311622-2509) Compound EHMT2 PEP EHMT1 PEP EHMT2 ICW No. (IC50 µM) (IC50 µM) (IC50 µM) 245 D D D 246 C B C 247 C C D 248 D C D 249 C B C 250 D C D 251 C B C 252 C B C 253 D C D 254 D D D 255 A A B 256 A A B 257 C B C 258 C B C 259 D C D 260 C B D 261 C B D 262 A A A 263 D D D 264 D D D 266 D D D 267 D D D 268 D D D 269 A A B 270 D D D 271 C C D 273 D D D 274 D C D 275 D D D 276 C C C 278 A A B 279 A A C 280 D C D 282 A A A 284 A A A 285 A A A 286 A A A 287 C B C 288 A A B 289 A A A 291 C C C 292 B A B 293 B A C 294 A A C ey Docket No.: EPIZ-073/001WO (311622-2509) Compound EHMT2 PEP EHMT1 PEP EHMT2 ICW No. (IC50 µM) (IC50 µM) (IC50 µM) 295 C B C 296 B A C 297 D D D 298 D D D 299 D C D 300 B A B 301 C C D 302 D D D 303 C C D 304 B B D 305 B C D 306 C C D 307 A A B 308 C B D 309 C B D 310 C C D 311 D D D 312 D D D 313 B B C 314 A A B 315 B B C 316 A A B 317 A A A 318 B B B 319 A A A 320 A A B 321 A A A 322 A A B 323 A A B 324 B B C 325 A A B 326 A A A 327 A A A 328 A A A 329 A A A 330 A A A 331 A A B 332 A A ND 333 A A ND 334 A A ND 386 A A A Attorney Docket No.: 73/001WO (311622-2509) The invention can be embodied in other ic forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than ng on the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Attorney Docket No.: EPIZ-073/001WO (311622-2509)

Claims (1)

What is claimed is:

1. A compound of Formula (I0), (II0), (III0), or (IV0): (I0), X5 R14 X14 N X6 R7 (II0), R8 X8 X5 R14 R9 N X6 R7 (III0), or (IV0), or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein X1 is N or CR2; X2 is N or CR3; X3 is N or CR4; X4 is N or CR5; X5 is N or CH; X6 is N or CR15; X7 is N or CH; X8 is NR13 or 2; one of X13 and X14 independently is NR8R9, and the other is R10; Attorney Docket No.: EPIZ-